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Quantification of Gastrointestinal Liquid Volumes and Distribution Following a 240 mL Dose of Water in the Fasted State
Abstract
The rate and extent of drug dissolution and absorption from solid oral dosage forms is highly dependent upon the volumes and distribution of gastric and small intestinal water. However, little is known about the time courses and distribution of water volumes in vivo in an undisturbed gut. Previous imaging studies offered a snapshot of water distribution in fasted humans and showed that water in the small intestine is distributed in small pockets. This study aimed to quantify the volume and number of water pockets in the upper gut of fasted healthy humans following ingestion of a glass of water (240 mL, as recommended for Bioavailability/Bioequivalence (BA/BE) studies), using recently validated non invasive Magnetic Resonance Imaging (MRI) methods. Twelve healthy volunteers underwent upper and lower abdominal MRI scans before drinking 240 mL (8 fluid ounces) of water. After ingesting the water, they were scanned at intervals for 2 hours. The drink volume, inclusion criteria and fasting conditions matched the international standards for BA/BE testing in healthy volunteers. The images were processed for gastric and intestinal total water volumes and for the number and volume of separate intestinal water pockets larger than 0.5 mL. The fasted stomach contained 35±7mL (mean±SEM) of resting water. Upon drinking, the gastric fluid rose to 242±9mL. The gastric water volume declined rapidly after that with a half emptying time (T50%) of 13±1 minutes. The mean gastric volume returned back to baseline 45 minutes after the drink. The fasted small bowel contained a total volume of 43±14mL of resting water. Twelve minutes after ingestion of water, small bowel water content rose to a maximum value of 94±24mL contained within 15±2 pockets of 6±2mL each. At 45 minutes, when the glass of water had emptied completely from the stomach, total intestinal water volume was 77±15mL distributed into 16±3 pockets of 5±1mL each. MRI provided unprecedented insights into the time course, number, volume and location of water pockets in the stomach and small intestine under conditions that represent standard BA/BE studies using validated techniques. These data add to our current understanding of gastrointestinal physiology and will help improve physiological relevance of in vitro testing methods and in silico transport analyses for prediction of bioperformance of oral solid dosage forms, particularly for low solubility BCS 2 and 4 compounds.
... In the fasting state, the small intestine is predominantly empty, digestive secretions are limited, and the few fluid pockets observed in the small intestine are largely static, allowing reliable visualisation and quantification of water in the small intestine using the high contrast of water in T2-weighted MRI sequences. [20][21][22][23]. ...
... To assess the suitability of manganese-labelled water for gastric emptying using T1-weighted MRI sequences, the data obtained in this study were compared with data from other MRI based gastric emptying studies, as shown in Fig. 6. [18,22,39] Although in the references T2weighted sequences were used to determine gastric emptying, it can be seen that all sequences yield very similar results. As expected, the gastric emptying of water seems not to be influenced by the addition of N = 8, mean). ...
... However, it is evident from previous studies using T2-weighted MRI, that water ingested in the fasted state is rapidly absorbed from the small intestine and that under these conditions water is only present as pockets or nests in the small intestine. [22,23] The rate of gastric water emptying is the rate-limiting step for water absorption and also determines the time course of absorption of highly permeable drugs such as caffeine and paracetamol. [8,48] It must therefore be assumed that the small intestinal content determined here, does not represent a pure water volume, but rather a wetted surface or length that has been in contact with or occupied by orally ingested manganese ions. ...
The transit and distribution pattern of fluids in the small intestine is a key parameter for the dissolution and absorption of drugs. Although some information is known about the small intestinal water content after administration of fluid volumes and meals, the intestinal transit of orally ingested fluids and solutions has been barely investigated. The aim of this three-arm, cross-over, 9-subject human study was to investigate the transit of orally ingested water in the small intestine under fasting and postprandial conditions using MRI. To identify the ingested water, manganese gluconate, which can be identified with T1-weighted MRI sequences, was added as a marker. Using Horos (DICOM software), quantification of the distribution of Mn2+ ions in the gastrointestinal tract in fasted versus fed state (standard meal by FDA guidance and a light meal) was possible. The distribution and approximate wetted intestinal length was very similar in the fasting and postprandial states, suggesting rapid transport of water ingested after a meal through the chyme-filled small intestine in continuation of the “Magenstrasse” (stomach road). In some subjects, manganese gluconate reached deeper parts of the small intestine even more quickly in the postprandial state than in the fasting arm of the study. A deeper understanding of the behaviour of solutes in the gastrointestinal tract is fundamental to a mechanistic explanation for the kinetic interaction between food and drug intake (food effects).
... GI fluid volume in humans (including children and adults) and rats has been investigated by means of magnetic resonance imaging (MRI) and positron emission tomography (PET) 6,[8][9][10][11] . However, GI fluid dynamics is complicated by multiple factors such as fluid flux across the intestinal membrane, GI transit, gastric emptying rate, and physiological environment (pH, sodium concentration, and carbohydrate, secretions such as salivary, gastric, gall bladder, and pancreatic secretions) 12 . ...
... Interestingly, luminal fluid volume reached a steady state within 30-60 min in a site-dependent manner. A similar tendency has been observed after the oral administration of water in humans 9,14 . However, the luminal fluid volume is regulated not only by the fluid absorption process but also by the secretion of biological fluid. ...
... Nevertheless, our present results indicate that the fluid secretion process is the major determinant of GI fluid dynamics and its regional differences. We recently reported that the GI fluid volume after administration of different volumes of purified water gradually decreased to a similar steady-state level 9 . Together with the present results, this supports the idea that the steady-state level of fluid in the GI tract is not affected by the administered fluid volume, but is defined by the homeostatic biological fluid secretion as well as fluid absorption processes. ...
The drug absorption profile is dependent on the luminal drug concentration, which in turn is influenced by the gastrointestinal (GI) fluid dynamics. In the present study, therefore, we aimed to examine the luminal fluid dynamics by kinetically analyzing fluid absorption and secretion along the GI tract in rats using the in situ closed-loop technique with non-absorbable fluorescein isothiocyanate-dextran 4000 (FD-4) and tritium water labeling ([ ³ H]water) under different osmotic conditions. We found that the luminal fluid volume in the jejunum and ileum, but not the colon, gradually decreased and reached a steady state. In contrast, [ ³ H]water almost completely disappeared in all intestinal regions. Kinetic analysis revealed the following rank order for the rate constant of fluid secretion: jejunum > ileum > colon, whereas a negligible regional difference was observed in the rate constant of fluid absorption. Fluid secretion under an isosmotic condition (300 mOsm/kg) was higher than that at 0 mOsm/kg in all intestinal regions, though no significant changes in fluid absorption were observed. Thus, the fluid secretion process appears to be the major determinant of the regional differences in GI fluid dynamics. Our findings indicate that the luminal fluid volume is altered as a result of water ingestion, absorption, and secretion, and finally reaches an apparent steady state, which is regulated mainly by the process of fluid secretion.
... In fasted state, the stomach pH ranges from 2 to 4 among healthy individuals [21]. As the conduit of random GE in a random discrete fluid packet fashion [22] and motilityrelated pancreatic and biliary draining [23] in the low buffer capacity setting, the proximal small intestine experiences the most dramatic pH fluctuations throughout the whole small intestine and tapers down distally. A large range of pH fluctuations (pH: 1.71-7.57) in the proximal small intestine has been reported in Hens et al. [21]. ...
... In particular, the small fluid pockets with time-varying volumes determine the amount of BCS class 2/4 drugs that can be dissolved in certain parts of the gut. Mudie et al. quantified the number and volume of those fluid pockets among 12 fasted healthy humans [22]. There is no sufficient clinical data regarding small intestinal volumes in the fed state. ...
... A notable application of ML/AI is to predict the plasma concentration-time profiles directly from a series of inputs. After grinded into small particles, drugs are emptied from the stomach into the duodenum in random discrete fluid pockets [22], mixed well with GI secretions, delivered via intestinal transit to the absorptive site, and finally absorbed at the duodenum or the jejunum. Traditional modeling of discontinuous fluid pocket emptying and GI transit, unstable GI secretion, limited GI fluid buffer capacity, and the impact of drug on local pH is quite challenging. ...
This review is a revisit of various oral drug absorption models developed in the past decades, focusing on how to incorporate the physiological dynamics in the upper gastrointestinal (GI) tract. For immediate-release oral drugs, GI absorption is a critical input of drug exposure and subsequent human body response, yet difficult to model largely due to the complex GI environment. One of the biggest hurdles lies at capturing the high within-subject variability (WSV) of bioavailability measures, which can be mechanistically explained by the GI physiological dynamics. A thorough summary of how GI dynamics is handled in the absorption models would promote the development of mechanism-based oral drug absorption models, aid in the design of clinical studies regarding dosing regimens and bioequivalence studies based on WSV, and advance the decision-making on formulation selection.
Graphical Abstract
... To emulate rapid alginate crosslinking and to facilitate experimentation, hydrogels were first internally crosslinked with CaCO 3 and glucono-δ-lactone and then analysed within a bath of 200 mM CaCl 2 /10 mM PEG-dithiol solution. Notably, the sharpest increase in modulus occurred during the first 10-15 min (Fig. 2e), further supporting the feasibility of gastric crosslinking at timeframes relevant to liquid retention within the stomach (time of 50% emptying: 15-30 min) 15,21 . LIFT hydrogels were then studied for their capacity to encapsulate therapeutic cargos of different length scales, using 155-kDa dextran as a model macromolecule and 20-or 100-nm polystyrene nanoparticles as model controlled-release nanoparticles. ...
... While LIFT hydrogel formation and mechanical properties were dependent on the proportion of gastric fluid volume, this may be diluted through greater volumes of crosslinker. The fasted stomach contains 25-35 ml of gastric fluid 21,41 , which after ingestion of a 200 ml crosslinker solution is diluted to 11-15%. This volume is less than the volume of a typical drink can (355 ml), and this proportion of gastric fluid is well within the range capable of crosslinking LIFT. ...
Pills are a cornerstone of medicine but can be challenging to swallow. While liquid formulations are easier to ingest, they lack the capacity to localize therapeutics with excipients nor act as controlled release devices. Here we describe drug formulations based on liquid in situ-forming tough (LIFT) hydrogels that bridge the advantages of solid and liquid dosage forms. LIFT hydrogels form directly in the stomach through sequential ingestion of a crosslinker solution of calcium and dithiol crosslinkers, followed by a drug-containing polymer solution of alginate and four-arm poly(ethylene glycol)-maleimide. We show that LIFT hydrogels robustly form in the stomachs of live rats and pigs, and are mechanically tough, biocompatible and safely cleared after 24 h. LIFT hydrogels deliver a total drug dose comparable to unencapsulated drug in a controlled manner, and protect encapsulated therapeutic enzymes and bacteria from gastric acid-mediated deactivation. Overall, LIFT hydrogels may expand access to advanced therapeutics for patients with difficulty swallowing.
... The present data show that the assumed gastrointestinal fluid volume is one of the key parameters in the present model (Fig. 5, Fig. 6). While GastroPlus™ suggests a physiology with "physiologically accurate values for compartment lengths, volumes, and radii" (Simu-lationsPlus, 2021), other applied physiologies were based on a magnetic resonance imaging study by Mudie et al. (2014). A recent publication has compared available literature data on small intestinal fluid volumes and showed not only high variations within the studies, but also remarkable differences between the different studies (Van der Veken et al., 2022). ...
... Moreover, the study by Van der Veken et al. (2022) has quantified fluid volumes in the small intestines of adolescents (12-16-year old), which resulted in more than double the volumes that had been reported by Mudie et al. in 21±0.6-year-old adults (average of 94±70 mL vs. 43±14 mL) (Mudie et al., 2014). The two studies, however, are difficult to compare due to, e.g., differences in the quantification method, study design, clinical condition of subjects, and fasting conditions. ...
... where k GE is the gastric emptying rate constant [1/h] at fasting conditions. The k GE varies both within and between individuals, and the literature average values fall within the 3-14 1/h range (Mudie et al., 2014;Grimm et al., 2017;Yamashita et al., 2013). For simplicity, all PK simulations in this study assumed the fixed k GE of 8 1/h. ...
... The PK of oral drugs taken in fed and fasted states depends on the drug's transit from the stomach to the small intestine (Koziolek et al., 2016). When an IR product is ingested with a glass of water at fasting conditions, the tiny solid particles and dissolved drug molecules leave the stomach with water according to first-order kinetics (Mudie et al., 2014;Grimm et al., 2017;Yamashita et al., 2013) Fig. 4. The influence of the gastric chyme emptying rate (GE fed ) and small intestinal transit rate (kT_SI) on the predicted steady-state PK profiles in a typical patient after 20 mg rivaroxaban administration QD under fed conditions. P eff was fixed at 3E-4 cm/s. ...
... Magnetic resonance imaging (MRI) stands as one of the most frequently utilised imaging techniques to evaluate the gastric transit and intestinal behaviour of dosage forms [24]. MRI offers real-time visualization of the environment surrounding the dosage form, such as stomach water content and intestinal wall contractions [25]. This unique capability makes MRI highly suitable for assessing the in vivo disintegration of oral dosage forms, providing a comprehensive understanding of their behaviour within the gastrointestinal tract [26,27]. ...
... The mean disintegration times for the SLS90 and SLS130 formulations were determined to be 7.2 ± 1.0 and 2.8 ± 0.8 min, respectively. Additionally, an alternative in vitro disintegration study was proposed to better simulate conditions found in vivo, by reducing the volume of media (the estimated liquid volume of an empty human stomach is typically around 50 mL to 100 mL) and eliminating intense gastric agitation [25]. For this purpose, the torus printlets were placed in the centre of petri dishes containing 50 mL of HCl 0.1 M at 37 • C. The modified disintegration tests using petri dishes yielded disintegration times of 25.5 ± 4.1 and 18.8 ± 1.9 min for the SLS90 and SLS130 formulations, respectively (Fig. 6). ...
... In our study, t max after intake of the tablet with 240 mL water was 30 ± 10 min; thus, it was consistent with published data on gastric emptying of the corresponding volume of water administered in clinical trials under fasted conditions. Based on previous MRI studies, it was shown that the gastric emptying of 240 mL of water can be observed within from 15 to 60 min [41], or within 45 min from the fasted stomach [42], though the interindividual variability of gastric water emptying indicates that the observed variability was in line with literature [41]. ...
... In healthy young volunteers, food is emptied from the stomach slower than water at a rate of about 2-4 kcal/min [46]. Furthermore, this study was performed in an upright position, whereas previous water gastric emptying studies, either in fasted or fed state conditions, have been conducted in a supine position [13,20,26,41,42]. Previous studies in fasted state have shown that changes in posture can have an influence on the intragastric distribution of a drug within the stomach [47,48]. ...
Because of the importance of gastric emptying for pharmacokinetics, numerous methods have been developed for its determination. One of the methods is the salivary tracer technique, which utilizes an ice capsule containing caffeine as a salivary tracer. Despite the ice capsule’s advantage in labeling ingested fluids with caffeine for subsequent salivary detection, its risk of premature melting before swallowing, and its complicated storage and preparation, limit its application, particularly in special populations (e.g., older people). For this reason, here, a compression-coated tablet was developed and validated against the ice capsule in a cross-over clinical trial. The two dosage forms were administered simultaneously to 12 volunteers in an upright position under fasted and fed state conditions. To distinguish the caffeine concentrations in saliva from each dosage form, regular type of caffeine (12C) was added to the tablet, while for the ice capsule 13C3 labelled caffeine was used. The salivary caffeine concentrations showed no statistically significant differences for the pharmacokinetic parameters tmax and AUC0→60 (p > 0.05). Thus, the new formulation is a useful tool for determining gastric emptying that can also be used in special populations.
... For adults, a standard weight of 70 kg was used. The fluid volume used in the in vitro setup was set at 50 mL for adults, based on a measured average small intestinal fluid volume (SIFV) of 43 mL [22]. For the paediatric population, in vitro fluid volumes were chosen based on the average SIFV measured by Van der Veken et al. [23]. ...
... Doses and volumes used in the age-dependent dissolution experiments with tacrolimus. SIFV were measured using magnetic resonance imaging (MRI) and published by Mudie et al.[22] for adults and Van der Veken et al.[23] for paediatric patients. For al (sub)populations, a 0.15 mg/kg dose was assumed. ...
Tacrolimus is a crucial immunosuppressant for organ transplant patients, requiring therapeutic drug monitoring due to its variable exposure after oral intake. Physiologically based pharmacokinetic (PBPK) modelling has provided insights into tacrolimus disposition in adults but has limited application in paediatrics. This study investigated age dependency in tacrolimus exposure at the levels of absorption, metabolism, and distribution. Based on the literature data, a PBPK model was developed to predict tacrolimus exposure in adults after intravenous and oral administration. This model was then extrapolated to the paediatric population, using a unique reference dataset of kidney transplant patients. Selecting adequate ontogeny profiles for hepatic and intestinal CYP3A4 appeared critical to using the model in children. The best model performance was achieved by using the Upreti ontogeny in both the liver and intestines. To mechanistically evaluate the impact of absorption on tacrolimus exposure, biorelevant in vitro solubility and dissolution data were obtained. A relatively fast and complete release of tacrolimus from its amorphous formulation was observed when mimicking adult or paediatric dissolution conditions (dose, fluid volume). In both the adult and paediatric PBPK models, the in vitro dissolution profiles could be adequately substituted by diffusion-layer-based dissolution modelling. At the level of distribution, sensitivity analysis suggested that differences in blood plasma partitioning of tacrolimus may contribute to the variability in exposure in paediatric patients.
... For instance, there was an imperfect homogenization of gastric distention levels among patients undergoing MRI (500-1000 ml) and CT (500 ml) examinations, which could potentially impact diagnostic performance [4,35]. However, due to the lengthy duration of MRI, the amount of liquid in the stomach may decrease during later stages of the procedure [36], potentially reducing the difference in stomach dilation between MRI and CT scans. This reduction could somewhat diminish the impact of imprecise levels of stomach distension on the diagnostic effectiveness of gastric cancer staging. ...
Purpose
To assess the value of orthogonal axial images (OAI) of MRI in gastric cancer T staging.
Methods
This retrospective study enrolled 133 patients (median age, 63 [range, 24–85] years) with gastric adenocarcinoma who underwent both CT and MRI followed by surgery. MRI lacking or incorporating OAI and CT images were evaluated, respectively. Diagnostic performance (accuracy, sensitivity, and specificity) for each T stage, overall diagnostic accuracy and rates of over- and understaging were quantified employing pathological T stage as a reference standard. The McNemar’s test was performed to compare the overall accuracy.
Results
Among patients with pT1–pT4 disease, MRI with OAI (accuracy: 88.7–94.7%, sensitivity: 66.7–93.0%, specificity: 91.5–100.0%) exhibited superior diagnostic performance compared to MRI without OAI (accuracy: 81.2–88.7%, sensitivity: 46.2–83.1%, specificity: 85.5–99.1%) and CT (accuracy: 88.0–92.5%, sensitivity: 53.3–90.1%, specificity: 88.7–98.1%). The overall accuracy of MRI with OAI was significantly higher (83.5%) than that of MRI without OAI (67.7%) (p < .001). However, there was no significant difference in the overall accuracy of MRI with OAI and CT (78.9%) (p = .35). The over- and understaging rates of MRI with OAI (12.0, 4.5%) were lower than those of MRI without OAI (21.8, 10.5%) and CT (12.8, 8.3%).
Conclusion
OAI play a pivotal role in the T staging of gastric cancer. MRI incorporating OAI demonstrated commendable performance for gastric cancer T-staging, with a slight tendency toward its superiority over CT.
... One possible explanation for the observed strong signal fluctuations could be the strongly fluctuating availability of water in the small and large intestines, which is well observed in the fasting state. 5,29,41 Another possible explanation is that the susceptibility artifact generated by iron oxide, which leads to local signal extinction, may have overshadowed the signal enhancement derived from manganese gluconate in the T1-weighted VIBE sequence. The contrasting effect of manganese gluconate could probably be improved at higher field strengths, but that needs further evaluation. ...
Nefecon, a targeted-release capsule formulation of budesonide approved for the reduction of proteinuria in adults with primary immunoglobulin A nephropathy, targets overproduction of galactose-deficient immunoglobulin A type 1 in the Peyer’s patches at the gut mucosal level. To investigate whether the commercial formulation of Nefecon capsules reliably releases budesonide to the distal ileum, a human study was conducted with test capsules reproducing the delayed-release function of Nefecon capsules. Caffeine was included in the test capsules as a marker for capsule opening in the gut since it appears rapidly in saliva after release from orally administered dosage forms. Magnetic resonance imaging with black iron oxide was used to determine the capsule’s position in the gut at the time caffeine was first measured in saliva and additionally to directly visualize dispersion of the capsule contents in the gut. In vitro dissolution results confirmed that the test capsules had the same delayed-release characteristics as Nefecon capsules. In 10 of 12 human volunteers, the capsule was demonstrated to open in the distal ileum; in the other two subjects, it opened just past the ileocecal junction. These results compared favorably with the high degree of variability seen in other published imaging studies of delayed-release formulations targeting the gut. The test capsules were shown to reliably deliver their contents to the distal ileum, the region with the highest concentration of Peyer’s patches.
... The considerable lengths of the human jejunum and ileum contribute to the existence of water pockets, which could have a notable impact on drug dissolution. According to Mudie and co-workers' study, the jejunum is estimated to contain around 13 mL of fluids, but in vivo, these volumes present as small, separate water pockets based on MRI data, potentially hindering the drug's ability to attain its equilibrium solubility (55). ...
Mechanistic modeling of in vitro experiments using metabolic enzyme systems enables the extrapolation of metabolic clearance for in vitro-in vivo predictions. This is particularly important for successful clearance predictions using physiologically based pharmacokinetic (PBPK) modeling. The concept of mechanistic modeling can also be extended to biopharmaceutics, where in vitro data is used to predict the in vivo pharmacokinetic profile of the drug. This approach further allows for the identification of parameters that are critical for oral drug absorption in vivo. However, the routine use of this analysis approach has been hindered by the lack of an integrated analysis workflow. The objective of this tutorial is to (1) review processes and parameters contributing to oral drug absorption in increasing levels of complexity, (2) outline a general physiologically based biopharmaceutic modeling workflow for weak acids, and (3) illustrate the outlined concepts via an ibuprofen (i.e., a weak, poorly soluble acid) case example in order to provide practical guidance on how to integrate biopharmaceutic and physiological data to better understand oral drug absorption. In the future, we plan to explore the usefulness of this tutorial/roadmap to inform the development of PBPK models for BCS 2 weak bases, by expanding the stepwise modeling approach to accommodate more intricate scenarios, including the presence of diprotic basic compounds and acidifying agents within the formulation.
... The gastric retention data were fitted with the power-exponential model (Eq. (1)), indicating a half-time of gastric emptying (t 1/2 ) of 14 min with a β-value of 1.1, which well replicated the data observed in humans (Mudie et al., 2014). The gastric retention ratios in relation to time in Fig. 3 describe the scene before the occurrence of 'housekeeper wave'. ...
... 1.61-1.89 g/L at 22°C) and the volume of gastric secretion (ranging from 215 mL within a single meal to 2000 mL daily; ICRP, 2002;Mudie et al., 2014), the Panel considered that full dissolution of the proposed food additive is to be expected in foods and/or in the GI tract and that ingested particles (if any) would not persist. Therefore, the Panel concluded there is no concern with regard to the potential presence of small particles, including nanoparticles, in the proposed food additive and considered that the risk assessment can be performed following the EFSA Guidance for submission for food additive evaluations (EFSA ANS Panel, 2012). ...
The EFSA Panel on Food Additive and Flavourings (FAF Panel) provides a scientific opinion on the safety of a new process to produce steviol glycosides by fermentation of simple sugars using a genetically modified strain of Yarrowia lipolytica (named Y. lipolytica VRM). The manufacturing process may result in impurities different from those that may be present in the other steviol glycosides E 960a‐d, therefore the Panel concluded that separate specifications are required for the food additive produced as described in the current application. Viable cells and DNA from the production strain are not present in the final product. The Panel considered that the demonstration of the absence of kaurenoic acid in the proposed food additive, using a method with a limit of detection (LOD) of 0.3 mg/kg, is adequate to dispel the concerns for potential genotoxicity. Given that all steviol glycosides follow the same metabolic pathways, the Panel considered that the current steviol glycosides would fall within the same group of substances. Therefore, the Panel considered that the already existing data on rebaudioside M and structurally related steviol glycosides are sufficient, and a similar metabolic fate and toxicity is expected for the food additive. The results from the bacterial reverse mutation assay and the in vitro micronucleus assay were negative and indicated absence of genotoxicity from the food additive. The existing acceptable daily intake (ADI) of 4 mg/kg body weight (bw) per day, expressed as steviol equivalents, was considered to be applicable to the proposed food additive. The Panel concluded that there is no safety concern for steviol glycosides, predominantly Rebaudioside M, produced by fermentation using Y. lipolytica VRM, to be used as a food additive at the proposed uses and use levels.
... These physiological parameters are integrated into the softwarespecific advanced compartmental absorption and transit (ACAT) model of the GI tract and accounted for in a series of differential equations used to simulate the dynamic processes a drug undergoes in the body after peroral administration [29,30]. Physiological parameters describing a healthy human representative in the fasted state were kept at the software default values, except for the % fluid volumes in the small intestine (23%) and colon (0.5%), which were decreased from the default 40% and 10% to 23% and 0.5% [31], respectively, to account for the much smaller GI volumes in vivo [32][33][34]. To account for postbariatric surgery changes in physiological conditions, the ACAT model parameters were manually adjusted, i.e., gastric volume was decreased from default 50 to 10 mL, corresponding to 20% of the presurgery gastric volume [35,36], and gastric transit time was decreased from default 0.25 to 0.12 h [37,38]. ...
Postbariatric altered gastrointestinal (GI) anatomy/physiology may significantly harm oral drug absorption and overall bioavailability. In this work, sildenafil, the first phosphodiesterase-5 (PDE5) inhibitor, was investigated for impaired postbariatric solubility/dissolution and absorption; this research question is of particular relevance since erectile dysfunction (ED) is associated with higher body mass index (BMI). Sildenafil solubility was determined both in vitro and ex vivo, using pre- vs. postsurgery gastric contents aspirated from patients. Dissolution tests were done in conditions mimicking the stomach before surgery, after sleeve gastrectomy (post-SG, pH 5), and after one anastomosis gastric bypass (post-OAGB, pH 7). Finally, these data were included in physiologically based pharmacokinetic (PBPK) modelling (GastroPlus®) to simulate sildenafil PK before vs. after surgery. pH-dependent solubility was demonstrated with low solubility (0.3 mg/mL) at pH 7 vs. high solubility at pH 1–5, which was also confirmed ex vivo with much lower solubility values in postbariatric gastric samples. Hampered dissolution of all sildenafil doses was obtained under post-OAGB conditions compared with complete (100%) dissolution under both presurgery and post-SG conditions. PBPK simulations revealed delayed sildenafil absorption in postbariatric patients (increased tmax) and reduced Cmax, especially in post-OAGB patients, relative to a presurgery state. Hence, the effect of bariatric surgery on sildenafil PK is unpredictable and may depend on the specific bariatric procedure. This mechanistically based analysis suggests a potentially undesirable delayed onset of action of sildenafil following gastric bypass surgery.
... The filling and emptying of the duodenum were done with water and therefore its movement was realized by connecting the tube to a 50 ml syringe. For emptying the duodenum, 25 ml of the water was suctioned out of it, representing a reduction of 8.6% of its total volume, in agreement with other studies (Mudie et al 2014, Waal et al 2020. In both states, full (control) and empty, measurements with a 3 T MRI scanner (Biograph mMR, Siemens Healthineers, Germany) were conducted using a T1 vibe Dixon sequence with a resolution of (1 × 1 × 1) mm 3 to measure the duodenum shape as its distance to the pancreas. ...
Objective: Carbon ion radiotherapy is a promising radiation technique for malignancies like pancreatic cancer. However, organs’ motion imposes challenges for achieving homogeneous dose delivery. In this study, an anthropomorphic Pancreas Phantom for Ion-beam Therapy (PPIeT) was developed to simulate breathing and gastrointestinal motion during radiotherapy.
Approach: The developed phantom contains a pancreas, two kidneys, a duodenum, a spine and a spinal cord. The shell of the organs was 3D printed and filled with agarose-based mixtures. Hounsfield Units (HU) of PPIeTs’ organs were measured by CT. The pancreas motion amplitude in cranial-caudal (CC) direction was evaluated from patients’ 4D CT data. Motions within the obtained range were simulated and analyzed in PPIeT using MRI. Additionally, GI motion was mimicked by changing the volume of the duodenum and quantified by MRI. A patient-like treatment plan was calculated for carbon ions, and the phantom was irradiated in a static and moving condition. Dose measurements in the organs were performed using an ionization chamber and dosimetric films.
Main results: PPIeT presented tissue equivalent HU and reproducible breathing-induced CC displacements of the pancreas between (3.98±0.36) mm and a maximum of (18.19±0.44) mm. The observed maximum change in distance of (14.28±0.12) mm between pancreas and duodenum was consistent with findings in patients. Carbon ion irradiation revealed homogenous coverage of the virtual tumor at the pancreas in static condition with a 1 % deviation from the treatment plan. Instead, the dose delivery during motion with the maximum amplitude yielded an underdosage of 21 % at the target and an increased uncertainty by two orders of magnitude.
Significance: A dedicated phantom was designed and developed for breathing motion assessment of dose deposition during carbon ion radiotherapy. PPIeT is a unique tool for dose verification in the pancreas and its organs at risk during end-to-end tests.
... A typical dose of CEL is 100 to 200 mg given BD (twice a day) with or without food (https://go.drugbank.com/drugs/DB00482). We considered the highest single oral dose, 200 mg CEL, and the lowest water content: the 35 ml of an empty stomach 77 .Thus, the stomach is a supersaturated system with CEL concentration 1650 times higher than its experimental equilibrium solubility (3.46 mg L −1 ) 27 . Even considering half the dose of CEL and administration of the drug with water, the CEL concentration would still be supersaturated in the stomach. ...
The propensity of poorly water-soluble drugs to aggregate at supersaturation impedes their bioavailability. Supersaturated amorphous drug-salt-polymer systems provide an emergent approach to this problem. However, the effects of polymers on drug-drug interactions in aqueous phase are largely unexplored and it is unclear how to choose an optimal salt-polymer combination for a particular drug. Here, we describe a comparative experimental and computational characterization of amorphous solid dispersions containing the drug celecoxib, and a polymer, polyvinylpyrrolidone vinyl acetate (PVP-VA) or hydroxypropyl methylcellulose acetate succinate, with or without Na⁺/K⁺ salts. Classical models for drug-polymer interactions fail to identify the best drug-salt-polymer combination. In contrast, more stable drug-polymer interaction energies computed from molecular dynamics simulations correlate with prolonged stability of supersaturated amorphous drug-salt-polymer systems, along with better dissolution and pharmacokinetic profiles. The celecoxib-salt-PVP-VA formulations exhibit excellent biopharmaceutical performance, offering the prospect of a low-dosage regimen for this widely used anti-inflammatory, thereby increasing cost-effectiveness, and reducing side-effects.
... The observed dipyridamole precipitation rate in aqueous buffer pH 6.5 was found to be independent of how the pH was shifted (setting II and III), with an average value of 1.3 ± 0.4 mg/min for the empirical precipitation rate constant ( Fig. 3a and b). In terms of in vivo relevance, the gradual pH shift mimics the fasted-state gastric emptying profile more closely (t ½ = 13 ± 1 min for 240 mL of water) (40). Because the gradual pH shift merely introduced a lag phase for the drug precipitation, which was initiated at pH 6.5 producing a similar precipitation rate as compared to experiments using a fast pH shift, it may be argued that the slow pH shift, at least in this case, complicated the dissolution model without adding supplementary information. ...
... It has been shown that apples contain 2.23E+05 particles/g of small MPs (Oliveri Conti et al., 2020). With the intake of only one apple (cca 100 g) for every 250 mL gastric fluid in adults (Mudie et al., 2014) or 25 mL of gastric fluid in children (Van der Veken et al., 2022), transient concentration of small size MPs can result in around 9.2E+02 to 9.2E+03 particles/mL. This transient peak concentrations upon ingestion of food contaminated with high number of MPs were mimicked in our study. ...
Human ingestion of microplastics (MPs) is common and inevitable due to the widespread contamination of food items, but implications on the gastric digestion of food proteins are still unknown. In this study, the interactions between pepsin and polystyrene (PS) MPs were evaluated by investigating enzyme activity and conformation in a simulated human gastric environment in the presence or absence of PS MPs. The impact on food digestion was also assessed by monitoring the kinetics of protein hydrolysis through static in vitro gastric digestion of cow's milk contaminated with PS. The binding of pepsin to PS showed that the surface chemistry of MPs dictates binding affinity. The key contributor to pepsin adsorption seems to be π-π interactions between the aromatic residues and the PS phenyl rings. During quick exposure (10 min) of pepsin to increasing concentrations (222, 2219, 22188 particles/mL) of 10 μm PS (PS10) and 100 μm PS (PS100), total enzymatic activities were not affected remarkably. However, upon prolonged exposure at 1 and 2 h, preferential binding of pepsin to the small, low zeta-potential PS caused structural changes in the protein which led to a significant reduction of its activity. Digestion of cow's milk mixed with PS10 resulted in transient accumulation of larger peptides (10-35 kDa) and reduced bioavailability of short peptides (2-9 kDa) in the gastric phase. This, however, was only observed at extremely high PS10 concentration (0.3 mg/mL or 5.46E+05 particles/mL). The digestion of milk peptides, bound preferentially over pepsin within the hard corona on the PS10 surface, was delayed up to 15 min in comparison to bulk protein digestion. Intact caseins, otherwise rapidly digested, remained bound to PS10 in the hard corona for up to 15 min. This work presents valuable insights regarding the interaction of MPs, food proteins, and pepsin, and their dynamics during gastric digestion.
... Gastric resistance of enteric coating was evaluated for coated tablets containing the DLM edisylate ASD. For the pH-shift experiments described above, release testing in the gastric compartment was generally evaluated for 30-60 min, reflecting the gastric emptying time in the fasted state (15-60 min) (Grimm et al., 2018;Mudie et al., 2014). However, in the presence of food, the gastric emptying time changes and is within the range of 2-5 h, leading to a prolonged gastric residence time (Al-Gousous et al., 2017;Chen et al., 2008;Dressman et al., 1990;Kalantzi et al., 2006). ...
Recent work has highlighted that amorphous solid dispersions (ASDs) containing delamanid (DLM) and an enteric polymer, hypromellose phthalate (HPMCP), appear to be susceptible to crystallization during immersion in simulated gastric fluids. The goal of this study was to minimize contact of the ASD particles with the acidic media via application of an enteric coating to tablets containing the ASD intermediate, and improve the subsequent drug release at higher pH conditions. DLM ASDs were prepared with HPMCP and formulated into a tablet that was then coated with a methacrylic acid copolymer (Acryl EZE II®). Drug release was studied in vitro using a two-stage dissolution test where the pH of the gastric compartment was altered to reflect physiological variations. The medium was subsequently switched to simulated intestinal fluid. The gastric resistance time of the enteric coating was probed over the pH range of 1.6-5.0. The enteric coating was found to be effective at protecting the drug against crystallization in pH conditions where HPMCP was insoluble. Consequently, the variability in drug release following gastric immersion under pH conditions reflecting different prandial states was notably reduced when compared to the reference product. These findings support closer examination of the potential for drug crystallization from ASDs in the gastric environment where acid-insoluble polymers may be less effective as crystallization inhibitors. Further, addition of a protective enteric coating appears to provide a promising remediation strategy to prevent crystallization at low pH environments, and may mitigate variability associated with prandial state that arises due to pH changes.
... It has been shown that apples contain 2.23E+05 particles/g of small MPs (Oliveri Conti et al., 2020). With the intake of only one apple (cca 100 g) for every 250 mL gastric fluid in adults (Mudie et al., 2014) or 25 mL of gastric fluid in children (Van der Veken et al., 2022), transient concentration of small size MPs can result in around 9.2E+02 to 9.2E+03 particles/mL. This transient peak concentrations upon ingestion of food contaminated with high number of MPs were mimicked in our study. ...
... Water gastric emptying has extensively been studied in healthy adults under fed and fasted state conditions (Schneider et al., 2016). Under fasted conditions, gastric emptying of non-caloric fluids starts almost immediately after ingestion (Mudie et al., 2014) and, interestingly, the same pattern also occurs in the fed state, where non-caloric fluids are emptied as fast as under fasted conditions (Grimm et al., 2017). This effect is known as "Magenstraße" ("stomach road") and describes the fast emptying of liquids from the fed stomach regardless of the caloric content and texture of the meal (Koziolek et al., 2014. ...
The purpose of this review is to summarize the current knowledge on three physiological determinants of oral drug absorption, i.e., gastric emptying, volumes and composition of luminal fluids, and intestinal permeability, in the advanced age population, so that potential knowledge gaps and directions for further research efforts are identified. Published data on gastric emptying rates in older people are conflicting. Also, there are significant knowledge gaps, especially on gastric motility and emptying rates of drugs and of non-caloric fluids. Compared with younger adults, volumes of luminal contents seem to be slightly smaller in older people. Our understanding on the impact of advanced age on luminal physicochemical characteristics is, at best, very limited, whereas the impact of (co)morbidities and geriatric syndromes in the advanced age population has not been addressed to date. The available literature on the effect of advanced age on intestinal permeability is limited, and should be approached with caution, primarily due to the limitations of the experimental methodologies used.
Microplastics have been detected in various food types, suggesting inevitable human exposure. A major fraction may originate from aerial deposition and could be contaminated by ubiquitous pollutants such as polycyclic aromatic hydrocarbons (PAHs). While data on the sorption of pollutants to microplastics are abundant, the subsequent desorption in the gastrointestinal tract (GIT) is less understood. This prompted us to systematically investigate the release of microplastics-sorbed PAHs at realistic loadings (44–95 ng/mg) utilizing a physiology-based in vitro model comprising digestion in simulated saliva, gastric, and small and large intestinal fluids. Using benzo[a]pyrene as a representative PAH, desorption from different microplastics based on low density polyethylene (LDPE), thermoplastic polyurethanes (TPUs), and polyamides (PAs) was investigated consecutively in all four GIT fluid simulants. The cumulative relative desorption (CRD) of benzo[a]pyrene was negligible in saliva simulant but increased from gastric (4 ± 1% – 15 ± 4%) to large intestinal fluid simulant (21 ± 1% – 29 ± 6%), depending on the polymer type. CRDs were comparable for ten different microplastics in the small intestinal fluid simulant, except for a polydisperse PA-6 variant (1–10 μm), which showed an exceptionally high release (51 ± 8%). Nevertheless, the estimated contribution of microplastics-sorbed PAHs to total human PAH dietary intake was very low (≤0.1%). Our study provides a systematic data set on the desorption of PAHs from microplastics in GIT fluid simulants.
In the early days of anaesthesia, the fasting period for liquids was kept short. By the mid-20th century ‘nil by mouth after midnight’ had become routine as the principles of the management of ‘full stomach’ emergencies were extended to include elective healthy patients. Back then, no distinction was made between the withholding of liquids and solids. Towards the end of the last century, recommendations of professional anaesthesiology bodies began to reduce the fasting time of clear liquids to 2 h. This reduction in fasting time was based on the understanding that gastric emptying of clear liquids is rapid, exponential, and proportional to the current filling state of the stomach. Furthermore, there was no evidence of a link between drinking clear liquids and the risk of aspiration. Indeed, most instances of aspiration are caused by failure to identify aspiration risk factors and adjust the anaesthetic technique accordingly. In contrast, long periods of liquid withdrawal cause discomfort and may also lead to serious postoperative complications. Despite this, more than two decades after the introduction of the 2 h limit, patients still fast for a median of up to 12 h before anaesthesia, mainly because of organisational issues. Therefore, some hospitals have decided to allow patients to drink clear liquids within 2 h of induction of anaesthesia. Well-designed clinical trials should investigate whether these concepts are safe in patients scheduled for anaesthesia or procedural sedation, focusing on both aspiration risk and complications of prolonged fasting.
There remains a disconnect in plant breeding between increasing nutrient levels in crops at time of harvest and increasing bioaccessible levels of those nutrients during digestion. This study aims to develop and compare simulated digestion models for use in plant breeding and examine bioaccessible nutrient levels in common bean samples with differing seed coat coloration and patterning. The highest trait values (starch and protein hydrolysis, total phenolics, and antioxidant power) were observed from more dynamic digestion models, but even simple dynamic models showed higher trait values than a commonly used static digestion model. The use of these models provided insight on nutrient bioaccessibility; e.g., differences were observed during digestion between common bean genotypes for protein hydrolysis and between growing environments for both total phenolics and protein hydrolysis. Together, these results inform potential future pathways for applying simulated digestion models in plant breeding to improve bioaccessible nutrient levels in crops.
The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of naringenin [FL‐no: 16.132] as a new flavouring substance, in accordance with Regulation (EC) No 1331/2008. No other substances with sufficient structural similarity have been identified in existing FGEs that could be used to support a read‐across approach. The information provided on the manufacturing process, the composition and the stability of [FL‐no: 16.132] was considered sufficient. From studies carried out with naringenin, the Panel concluded that there is no concern with respect to genotoxicity. The use of naringenin as a flavouring substance at added portions exposure technique (APET) exposure levels is unlikely to pose a risk for drug interaction. For the toxicological evaluation of naringenin, the Panel requested an extended one‐generation toxicity study on naringenin, in line with the requirements of the Procedure and to investigate the consequence of a possible endocrine‐disrupting activity. The Panel considered that changes in thymus weight, litter size, post‐implantation loss and a consistent reduced pup weight in the high‐dose F2 generation could not be dismissed and selected therefore, the mid‐dose of 1320 mg/kg body weight (bw) per day for the parental males as the no observed adverse effect level (NOAEL) of the study. The exposure estimates for [FL‐no: 16.132] (31,500 and 50,000 μg/person per day for children and adults, respectively) were above the threshold of toxicological of concern (TTC) for its structural class (III). Using the NOAEL of 1320 mg/kg bw per day at step A4 of the procedure, margins of exposure (MoE) of 1590 and 630 could be calculated for adults and children, respectively. Based on the calculated MoEs, the Panel concluded that the use of naringenin as a flavouring substance does not raise a safety concern.
This work shows the utilization of a physiologically based biopharmaceutics model (PBBM) to mechanistically explain the impact of diverse food types on the pharmacokinetics (PK) of isoniazid (INH) and acetyl-isoniazid (Ac-INH). The model was established and validated using published PK profiles for INH along with a combination of measured and predicted values for the physico-chemical and biopharmaceutical propertied of INH and Ac-INH. A dedicated ontogeny model was developed for N-acetyltransferase 2 (NAT2) in human integrating Michaelis Menten parameters for this enzyme in the physiologically based pharmacokinetic (PBPK) model tissues and in the gut, to explain the pre-systemic and systemic metabolism of INH across different acetylator types. Additionally, a novel equation was proposed to calculate the luminal drug degradation related to the presence of reducing sugars, using individual sugar molar concentrations in the meal. By incorporating luminal degradation into the model, adjusting bile salt concentrations and gastric emptying according to food type and quantity, the PBBM was able to accurately predict the negative effect of carbohydrate-rich diets on the PK of INH.
Introduction
The herbal preparation STW 5 ameliorates functional dyspepsia partly by relaxing smooth muscle of the proximal stomach, thus improving gastric accommodation. We explored the unknown pathways responsible for this effect by testing targets known to modulate gastric smooth muscle relaxation.
Methods
STW 5‐induced relaxation of smooth muscle strips from guinea pig gastric corpus before and after pharmacological interventions were recorded with force transducers in an organ bath. ORAI1 mRNA expression was tested in the proximal stomach.
Key Results
Blockade of Ca ²⁺ ‐activated K ⁺ and Cl ⁻ channels, voltage‐gated L‐ or T‐type Ca2+ channels, TRPA1‐, TRPV1‐, adenosine or 5‐HT 4 receptors, antagonizing ryanodine receptors, inhibiting cyclooxygenase or sarcoplasmic reticulum calcium ATPase did not affect STW 5‐evoked relaxation. Likewise, protein‐kinase A or G were not involved. However, the relaxation evoked by STW 5 was significantly reduced by phorbol‐12‐myristat‐13‐acetat, an activator of protein‐kinase C, by 2‐ aminoethyldiphenylborinate, an inhibitor of the IP3 receptor‐mediated Ca ²⁺ release from the sarcoplasmic reticulum or by SKF‐96365, a nonselective store‐operated calcium entry (SOCE) blocker. Furthermore, the mixed TRPC3/SOCE inhibitor Pyr3, but not the selective TRPC3 blocker Pyr10, reduced the effect of STW 5. Finally, BTP2, a potent blocker of ORAI‐coupled SOCE, almost abolished STW 5‐evoked relaxation. Expression of ORAI1 could be demonstrated in the corpus/fundus.
Conclusions & Inferences
STW 5 inhibited SOCE, most likely ORAI channels, which are modulated by IP3‐ and PKC‐dependent mechanisms. Our findings impact on the design of drugs to induce muscle relaxation and help identify phytochemicals with similar modes of actions to treat gastrointestinal disturbances.
Recent publications by Benet and coworkers, Korzekwa and Nagar, and Rowland et al. signal disagreement regarding the use of Kirchhoff’s laws in combining pharmacokinetic parameters, especially clearances and rate constants. Here, it is pointed out that Kirchhoff’s laws as applied to pharmacokinetics simply assert that concentrations are well defined and that molar or mass balances hold. The real issue is how to combine parameters for clearance processes in sequence, which may be reversible, irreversible, or even active in either or both directions. It is also demonstrated that Kirchhoff’s laws cannot be used to resolve contradictory results observed in liver transport and clearance. Finally, a simple argument is provided relating nonlinear clearance to apparently anomalous bioavailability observations.
Skeletal muscle protein levels are governed by the relative rates of muscle protein synthesis (MPS) and breakdown (MPB). The mechanisms controlling these rates are complex, and their integrated behaviors are challenging to study through experiments alone. The purpose of this study was to develop and analyze a kinetic model of leucine-mediated mTOR signaling and protein metabolism in the skeletal muscle of young adults. Our model amalgamates published cellular-level models of the IRS1-PI3K-Akt-mTORC1 signaling system and of skeletal-muscle leucine kinetics with physiological-level models of leucine digestion and transport and insulin dynamics. The model satisfactorily predicts experimental data from diverse leucine feeding protocols. Model analysis revealed that total levels of p70S6K are a primary determinant of MPS, insulin signaling substantially affects muscle net protein balance via its effects on MPB, and p70S6K-mediated feedback of mTORC1 signaling reduces MPS in a dose-dependent manner.
Potassium (K ⁺ ) is the main intracellular cation in the body. Elevated K ⁺ levels (hyperkalemia) increase the risk of life‐threatening arrhythmias and sudden cardiac death. However, the details of K ⁺ homeostasis and the effects of orally administered K ⁺ binders, such as sodium zirconium cyclosilicate (SZC), on K ⁺ redistribution and excretion in patients remain incompletely understood. We built a fit‐for‐purpose systems pharmacology model to describe K ⁺ homeostasis in hyperkalemic subjects and capture serum K ⁺ (sK ⁺ ) dynamics in response to acute and chronic administration of SZC. The resulting model describes K ⁺ distribution in the gastrointestinal (GI) tract, blood, and extracellular and intracellular spaces of tissue, renal clearance of K ⁺ , and K ⁺ –SZC binding and excretion in the GI tract. The model, which was fit to time‐course sK ⁺ data for individual patients from two clinical trials, accounts for bolus delivery of K ⁺ in meals and oral doses of SZC. The virtual population of patients derived from fitting the model to these trials was then modified to predict the SZC dose–response and inform clinical trial design in two new applications: emergency lowering of sK ⁺ in severe hyperkalemia and prevention of hyperkalemia between dialysis sessions in patients with end‐stage chronic kidney disease. In both cases, the model provided novel and useful insight that was borne out by the now completed clinical trials, providing a concrete case study of fit‐for‐purpose, model‐informed drug development after initial approval of a drug.
Polysaccharide aerogels have emerged as a highly promising technology in the field of oral drug delivery. These nanoporous, ultralight materials, derived from natural polysaccharides such as cellulose, starch, or chitin, have significant potential in colonic drug delivery due to their unique properties. The particular degradability of polysaccharide-based materials by the colonic microbiota makes them attractive to produce systems to load, protect, and release drugs in a controlled manner, with the capability to precisely target the colon. This would allow the local treatment of gastrointestinal pathologies such as colon cancer or inflammatory bowel diseases. Despite their great potential, these applications of polysaccharide aerogels have not been widely explored. This review aims to consolidate the available knowledge on the use of polysaccharides for oral drug delivery and their performance, the production methods for polysaccharide-based aerogels, the drug loading possibilities, and the capacity of these nanostructured systems to target colonic regions.
Surfactants are a diverse group of compounds that share the capacity to adsorb at the boundary between distinct phases of matter. They are used as pharmaceutical excipients, food additives, emulsifiers in cosmetics, and as household/industrial detergents. This review outlines the interaction of surfactant-type excipients present in oral pharmaceutical dosage forms with the intestinal epithelium of the gastrointestinal (GI) tract. Many surfactants permitted for human consumption in oral products reduce intestinal epithelial cell viability in vitro and alter barrier integrity in epithelial cell monolayers, isolated GI tissue mucosae, and in animal models. This suggests a degree of mis-match for predicting safety issues in humans from such models. Recent controversial preclinical research also infers that some widely used emulsifiers used in oral products may be linked to ulcerative colitis, some metabolic disorders, and cancers. We review a wide range of surfactant excipients in oral dosage forms regarding their interactions with the GI tract. Safety data is reviewed across in vitro, ex vivo, pre-clinical animal, and human studies. The factors that may mitigate against some of the potentially abrasive effects of surfactants on GI epithelia observed in pre-clinical studies are summarised. We conclude with a perspective on the overall safety of surfactants in oral pharmaceutical dosage forms, which has relevance for delivery system development.
Anatomical/physiological gastrointestinal changes after bariatric surgery may influence the fate of orally administered drugs.Since non-selective NSAIDs are not well-tolerated post-surgery, selective cyclooxygenase-2 (COX-2) inhibitors may be important for these patients. In this work we investigated celecoxib, etoricoxib and etodolac, for impaired post-bariatric solubility/dissolution and absorption. Solubility was studied in-vitro, and ex-vivoin aspirated gastric contents from patients pre- vs. post-surgery. Dissolution was studied in conditions simulating pre- vs. post-surgery stomach. Finally, the experimental solubility data were used in physiologically-based biopharmaceutics model (PBBM) (GastroPlus®) to simulate pre- vs. post-surgery celecoxib/etoricoxib/etodolac pharmacokinetic (PK) profiles.For etoricoxib and etodolac (but not celecoxib), pH-dependent solubility was demonstrated: etoricoxib solubility decreased ∼1000-fold, and etodolac solubility increased 120-fold, as pH increased from 1 to 7, which was also confirmed ex-vivo. Hampered etoricoxib dissolution and improved etodolac dissolution post-surgery was revealed. Tablet crushing, clinically recommended after surgery, failed to improve post-bariatric dissolution. PBBM simulations revealed significantly impaired etoricoxib absorption post-surgery across all conditions; for instance, 79% lower Cmax and 53% decreased AUC was simulated post-gastric bypass procedure, after single 120 mg dose. Celecoxib and etodolac maintained unaffected absorption after bariatric surgery.This mechanistically-based analysis suggests to prefer the acidic drug etodolac or the neutral celecoxib as selective COX-2 inhibitors, over the basic drug etoricoxib, after bariatric surgery.
There is a quest for a novel in vitro analytical methodology that is properly validated for the prediction of human oral absorption and bioaccumulation of organic compounds with no need of animal models. The traditional log P parameter might not serve to predict bioparameters accurately inasmuch as it merely accounts for the hydrophobicity of the compound, but the actual interaction with the components of eukaryotic cells is neglected. This contribution proposes for the first time a novel biomimetic microextraction approach capitalized on immobilized phosphatidylcholine as a plasma membrane surrogate onto organic polymeric sorptive phases for the estimation of human intestinal effective permeability of a number of pharmaceuticals that are also deemed contaminants of emerging concern in environmental settings. A comprehensive exploration of the conformation of the lipid structure onto the surfaces is undertaken so as to discriminate the generation of either lipid monolayers or bilayers or the attachment of lipid nanovesicles. The experimentally obtained biomimetic extraction data is proven to be a superb parameter against other molecular descriptors for the development of reliable prediction models of human jejunum permeability with R2 = 0.76, but the incorporation of log D and the number of aromatic rings in multiple linear regression equations enabled improved correlations up to R2 = 0.88. This work is expected to open new avenues for expeditious in vitro screening methods for oral absorption of organic contaminants of emerging concern in human exposomics.
The rate and extent of drug dissolution and absorption from a solid oral dosage form depend largely on the fluid volume along the gastrointestinal tract. Hence, a model built upon the gastric fluid volume profiles can help to predict drug dissolution and subsequent absorption. To capture the great inter- and intra-individual variability (IAV) of the gastric fluid volume in fasted human, a stochastic differential equation (SDE)-based mixed effects model was developed and compared with the ordinary differential equation (ODE)-based model. Twelve fasted healthy adult subjects were enrolled and had their gastric fluid volume measured before and after consumption of 240 mL of water at pre-determined intervals for up to 2 hours post ingestion. The SDE- and ODE-based mixed effects models were implemented and compared using extended Kalman filter algorithm via NONMEM. The SDE approach greatly improved the goodness of fit compared with the ODE counterpart. The proportional and additive measurement error of the final SDE model decreased from 14.4 to 4.10% and from 17.6 to 4.74 mL, respectively. The SDE-based mixed effects model successfully characterized the gastric volume profiles in the fasted healthy subjects, and provided a robust approximation of the physiological parameters in the very dynamic system. The remarkable IAV could be further separated into system dynamics terms and measurement error terms in the SDE model instead of only empirically attributing IAV to measurement errors in the traditional ODE method. The system dynamics were best captured by the random fluctuations of gastric emptying coefficient Kge.
Postoperative anastomotic leaks are the most feared complications after gastric surgery. For diagnostics clinicians mostly rely on clinical symptoms such as fever and tachycardia, often developing as a result of an already fully developed, i.e., symptomatic, surgical leak. A gastric fluid responsive, dual modality, electronic‐free, leak sensor system integrable into surgical adhesive suture support materials is introduced. Leak sensors contain high atomic number carbonates embedded in a polyacrylamide matrix, that upon exposure to gastric fluid convert into gaseous carbon dioxide (CO2). CO2 bubbles remain entrapped in the hydrogel matrix, leading to a distinctly increased echogenic contrast detectable by a low‐cost and portable ultrasound transducer, while the dissolution of the carbonate species and the resulting diffusion of the cation produces a markedly reduced contrast in computed tomography imaging. The sensing elements can be patterned into a variety of characteristic shapes and can be combined with nonreactive tantalum oxide reference elements, allowing the design of shape‐morphing sensing elements visible to the naked eye as well as artificial intelligence‐assisted automated detection. In summary, shape‐morphing dual modality sensors for the early and robust detection of postoperative complications at deep tissue sites, opening new routes for postoperative patient surveillance using existing hospital infrastructure is reported.
Food–drug interaction is one of the major factors that impact clinical pharmacokinetics in drug development. Unfortunately, the available in vitro and preclinical models do not appropriately predict food effects due to the complex mechanisms. It is recognized by the FDA that a food effect study should be conducted in the early clinical stage to inform the dosing paradigm and establish food effects risks in patients. Physiologically based biopharmaceutics modeling (PBBM) is a powerful tool to predict clinical PK by incorporating physiology-related and drug product-related factors in the mechanistic absorption model. PBBM has been utilized in various applications in drug development, such as biopharmaceutics risk assessment, bioequivalence safe space setup, and pH-mediated drug–drug interaction evaluation. The application of utilizing PBBM for food effect assessment has been tested and validated through many published case studies. In this chapter, an overview of food effects including current assessment practice, various food–drug interaction mechanisms, and clinical considerations is included. Thorough instruction on using PBBM to evaluate food effects is provided, followed by two detailed case studies. Though PBBM has shown potential in food effect prediction, it is still an evolving area, and current gaps and future directions are discussed.KeywordsFood effectPhysiologically based biopharmaceutics modeling (PBBM)Physiologically based pharmacokinetics modeling (PBPK)
Herbal beverages with antioxidant and prebiotic properties are promising nutraceutical candidates to prevent or cure various intestinal diseases that involve oxidative stress and/or imbalance of gut microbiota. In this study, partial chemical characterization of the small molecule (ethanol soluble) and polymeric (ethanol precipitated and TCA precipitated) fractions of two types of beverages (Centella asiatica beverages; decoction and infusion) from Centella asiatica were investigated. Fifty-two compounds with known record of antioxidant or anti-inflammation effect were identified in both beverages. All targeted fractions of two beverages had reducing capacity and free radical scavenging ability. The in vitro antioxidant capacity of both beverages and their individual fractions was further confirmed in H2O2 stressed Saccharomyces cerevisea models. However, the lipid peroxidation lessening ability was only observed in the small molecule fractions. The results suggested that different types of molecules in beverages can succeed via multiple mechanisms to reverse the oxidative stress in cells. In a separate experiment, both beverages could significantly retard the growth of the gastrointestinal pathogen Bacillus cereus. On the other hand, the CABs promoted growth of a well-known probiotic strain Lacticaseibacillus rhamnosus ATCC 53103 when tested individually as well as when grown together with Bacillus cereus. This study suggests that the beverages may balance antioxidant status as well as maintain quantity and diversity of microbiota to protect intestinal health. Additionally, a framework has been put forward to highlight the possible sites of intestine where an herbal beverage can act to prevent and cure some of the intestinal diseases.
Biorelevant dissolution tests of oral solid dosage forms open the gate to valid in vitro-in vivo predictions (IVIVP). A recently developed apparatus, PhysioCell, allows mimicking the fluid flow and pressure waves occurring in the human fasted stomach. In this work, we used the PhysioCell to perform IVIVP for vortioxetine immediate-release (IR) tablets: the originator (Brintellix) and generic product candidates (VORTIO). The dissolved drug was monitored in the gastric (StressCell) and intestinal (Collection Vessel) compartments that contained biorelevant media. Simulated intermittent gastric stress at 15 min and 'housekeeping wave' at 30 min increased the dissolution of Brintellix formulations only. A mechanistic model that best described the observations involved the first-order tablet disintegration with a stress-induced enhancement for Brintellix, dissolution of solid particles in the StressCell, and drug transfer to the Collection Vessel. Then, a semi-mechanistic pharmacokinetic model with dissolution parameters as inputs simulated vortioxetine plasma concentrations in healthy volunteers after single and multiple dosing of Brintellix. Despite different dissolution characteristics, VORTIO provided similar concentration profiles to the originator. In conclusion, PhysioCell dissolution tests, combined with semi-mechanistic IVIVP, can be successfully used to develop IR dosage forms exhibiting gastric stress-related effects.
Since the processes of dissolution and membrane permeation are affected by the water content in the gastrointestinal (GI) tract, the water dynamics in the GI tract is expected to have a significant impact on the absorption of orally administered drugs. Here, we aimed to develop a physiologically based fluid kinetic (PBFK) model using GI water kinetic parameters obtained from in situ closed-loop studies in rats in order to quantitatively predict GI water dynamics. By incorporating the experimentally measured site-specific parameters of GI water absorption and secretion into a GI compartment model, we developed a bottom-up PBFK model that successfully simulates the reported GI fluid dynamics in rats and humans observed using positron emission tomography and magnetic resonance imaging, respectively. The simulations indicate that the water volume in both the stomach and duodenum is transiently increased by water ingestion, while that in the intestine below the jejunum is unchanged and remains in a steady state in both rats and humans. Furthermore, sensitivity analysis of the effect of ingested water volume on the volume-time profiles of water in the GI tract indicated that the impact of ingested water is limited to the proximal part of the GI tract. Simulations indicated that changes in water kinetic parameters may alter the impact of the ingested water on GI fluid dynamics, especially in the proximal part. Incorporating this PBFK model into a physiologically based pharmacokinetic (PBPK) absorption model has the potential to predict oral drug absorption in a variety of GI water environments.
Encorafenib is a kinase inhibitor indicated for the treatment of patients with BRAF mutant melanoma and BRAF mutant metastatic colorectal cancer. To understand the effect of food and coadministration with a proton-pump inhibitor (PPI), in vitro, in vivo, and in silico data were generated to optimize the clinical dose, evaluate safety, and better understand the oral absorption process under these conditions. Study 1 evaluated the effect of food on the plasma pharmacokinetics, safety, and tolerability after a single oral dose of encorafenib 100 mg. Study 2 evaluated the same end points with coadministration of encorafenib and rabeprazole (PPI perpetrator). The in vitro gastrointestinal TIM-1 model was used to investigate the release of encorafenib and the amount available for absorption under different testing conditions (fasted, fed, and with the use of a PPI). The fasted, fed, and PPI states were predicted for the encorafenib commercial capsule in GastroPlus 9.8. In study 1, both AUCinf and AUClast decreased by 4% with the administration of a high-fat meal. The Cmax was 36% lower than with fasted conditions. All 3 exposure parameters in study 2 (AUCinf, AUClast, and Cmax) had mean changes of <10% when encorafenib was coadministered with a PPI. Using the in vitro gastrointestinal simulator TIM-1, the model demonstrated a similar release of drug, as the bioaccessible fraction, in the 3 conditions was equal (≥80%), predicting no PPI or food effect for this drug formulation. The modeling in GastroPlus 9.8 demonstrated complete absorption of encorafenib when formulated as an amorphous solid dispersion. To obtain these results, it was crucial to integrate the amorphous solubility of the drug that shows a 20-fold higher solubility at pH 6.8 compared with crystalline solubility. The increased amorphous solubility is likely the reason no PPI effect was observed compared with fasted state conditions. The prolongation in gastric emptying in the fed state resulted in delayed plasma Tmax for encorafenib. No dose adjustment is necessary when encorafenib is administered in the fed state or when coadministered with a PPI. Both the TIM-1 and physiologically based pharmacokinetic model results were consistent with the observed clinical data, suggesting that these will be valuable tools for future work.
The migrating motor complex (MMC) is a cyclic, recurring motility pattern that occurs in the stomach and small bowel during fasting; it is interrupted by feeding. The MMC is present in the gastrointestinal tract of many species, including humans. The complex can be subdivided into four phases, of which phase III is the most active, with a burst of contractions originating from the antrum or duodenum and migrating distally. Control of the MMC is complex. Phase III of the MMC with an antral origin can be induced in humans through intravenous administration of motilin, erythromycin or ghrelin, whereas administration of serotonin or somatostatin induces phase III activity with duodenal origin. The role of the vagus nerve in control of the MMC seems to be restricted to the stomach, as vagotomy abolishes the motor activity in the stomach, but leaves the periodic activity in the small bowel intact. The physiological role of the MMC is incompletely understood, but its absence has been associated with gastroparesis, intestinal pseudo-obstruction and small intestinal bacterial overgrowth. Measuring the motility of the gastrointestinal tract can be important for the diagnosis of gastrointestinal disorders. In this Review we summarize current knowledge of the MMC, especially its role in health and disease.
The purpose of this study was to establish a method for imaging the process of gastrointestinal (GI) absorption and subsequent biodistribution in the human body after oral drug administration, using positron emission tomography (PET) with 2-[(18)F]fluoro-2-deoxy-D-glucose ([(18)F]FDG). First, we developed a method to deliver the radiotracer safely into the stomach using soft gelatin capsules to avoid any significant exposure to the pharyngoesophageal region. Second, we performed pharmacokinetic (PK) analyses on time-radioactivity profiles in GI tissues and blood to calculate the gastric emptying and intestinal elimination rate constants and to estimate the fluid volume in the lumen of the small intestine from PET image analysis. This is the first study involving oral administration of a PET probe in humans, and the results demonstrate the high potential of PET technology to investigate the GI absorption and PK profiles of drugs in humans.
A biopharmaceutics drug classification scheme for correlating in vitro drug product dissolution and in vivo bioavailability is proposed based on recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling rate and extent of drug absorption. This analysis uses a transport model and human permeability results for estimating in vivo drug absorption to illustrate the primary importance of solubility and permeability on drug absorption. The fundamental parameters which define oral drug absorption in humans resulting from this analysis are discussed and used as a basis for this classification scheme. These Biopharmaceutic Drug Classes are defined as: Case 1. High solubility-high permeability drugs, Case 2. Low solubility-high permeability drugs, Case 3. High solubility-low permeability drugs, and Case 4. Low solubility-low permeability drugs. Based on this classification scheme, suggestions are made for setting standards for in vitro drug dissolution testing methodology which will correlate with the in vivo process. This methodology must be based on the physiological and physical chemical properties controlling drug absorption. This analysis points out conditions under which no in vitro-in vivo correlation may be expected e.g. rapidly dissolving low permeability drugs. Furthermore, it is suggested for example that for very rapidly dissolving high solubility drugs, e.g. 85% dissolution in less than 15 minutes, a simple one point dissolution test, is all that may be needed to insure bioavailability. For slowly dissolving drugs a dissolution profile is required with multiple time points in systems which would include low pH, physiological pH, and surfactants and the in vitro conditions should mimic the in vivo processes.(ABSTRACT TRUNCATED AT 250 WORDS)
We have previously used a magnetic resonance imaging (MRI) method to study gastric emptying of liquids. So far, however, it has not possible to assess solid gastric emptying with this technique.
To validate scintigraphically MRI as a method for measuring emptying of a mixed solid/liquid meal.
In eight healthy subjects, gastric emptying of a solid/liquid (SM) and a liquid meal (LM) of identical energy content and macronutrient composition was studied by scintigraphy and MRI for 120 minutes.
MRI and scintigraphy agreed with respect to emptying profiles (intraclass correlation coefficient (RI) SM: 0.988, RI, LM: 0.917), t1/2 (SMMRI: 129 (9), SMScinti: 123 (11) minutes, NS; LMMRI: 100 (7), LMScinti: 110 (8) minutes, NS) and AUC (SMMRI: 8999 (232), SMScinti: 8788 (277) min%, NS; LMMRI: 8819 (368), LMScinti: 8891 (321) min%, NS).
MRI can be used to measure reliably gastric emptying not only of liquid but also of mixed solid/liquid meals in humans.
To study the effects of posture and meal structure on gastric emptying and satiety, nine women ingested tomato soup and then immediately or 20 min later an egg sandwich, when seated and when supine. The lag time was not different, but the half-emptying time of the sandwich was 32% longer (P < 0.01) and the emptying rate after the lag phase was 39% slower (P < 0.01) when the subjects were supine than when they were seated. The half-emptying time of the soup was 50% longer (P < 0.01) when the subjects were supine and ingested the soup immediately before the sandwich than in the other three conditions. Postprandial hunger ratings recovered more slowly (P < 0.01) when the subjects ingested the soup 20 min before the sandwich than when they ingested the soup immediately before the sandwich. These results suggest that posture did not affect the intragastric distribution of the sandwich but affected propulsion of the meal into the intestine and that postprandial satiety was enhanced by the cumulative effect over time of a 20-min "head start" in stimulation of intestinal receptors by emptying of the soup.
Gastric contents empty from the stomach despite frequent changes in body position. The mechanism that maintains gastric emptying independent of position is poorly understood. The aim of this study was to determine the effects of body position on gastric emptying and motor function.
Twelve volunteers were investigated in seated position (SP) and upside-down position (UDP) after ingestion of 300 ml water. Magnetic resonance imaging provided a non-invasive assessment of gastric emptying and volumes, intragastric distribution and peristaltic function.
A marked difference in distal/proximal intragastric distribution between UDP and SP was present (7% versus 40%; p < 0.01). Gastric-emptying time was similar but emptying pattern was linear in UDP and exponential in SP. Peristalsis was slower in UDP than SP (2.75 versus 2.96 min-1; p < 0.01), but no correlation was found between peristaltic frequency and the rate of gastric emptying in either position. Postprandial volume response (gastric relaxation) was greater in UDP than SP (280 versus 250 ml; p < 0.05). A correlation was found between gastric relaxation and gastric-emptying time in SP (r2=0.46) but not in UDP.
The stomach maintains the rate of gastric emptying despite radical changes in body position and intragastric distribution of gastric contents. In SP, hydrostatic pressure (modulated by gastric tone) dictates the gastric emptying. In UDP, gastric emptying also appears to be mediated by continuous adaptation of gastric tone. These findings provide support for the hypothesis that the mechanism of gastric emptying resembles a "pressure pump" rather than a "peristaltic pump".
Background: Glucagon-like peptide-1 (GLP-1) has been shown to inhibit gastric emptying of a caloric load but the effect on a non-caloric load is unknown. Methods: Seven healthy men were studied after an over-night fast. Thirty min before the intake of 330 ml radioactively labeled water either GLD-I (0.75 pmol/kg/min) or saline was administered intravenously and continued for 75 min. Scintigraphic gastric emptying was performed for 45 min and plasma samples were obtained for analysis of vasopressin, sodium, osmolality, GLP-1, insulin, and glucose. In addition, electric field stimulation of human gastric muscle strips was done. Results: The median (range) percent water retained in the stomach, 45 min after intake of water, was 96% (68%-98%) and 12% (2%-42%) (P = 0.02) during infusion of GLP-1 and saline, respectively. Additionally, GLP-1 did not affect basal tune or contractile response of gastric muscle strips to electric field stimulation or acetylcholine (ACh). There was no change in plasma concentrations of vasopressin, sodium, or plasma osmolality during GLP-1 compared to saline infusion. Conclusion: GLP-1 has a profound inhibitory effect on the gastric emptying of water in man, but no short-term effect on water homeostasis. No effect was seen on contractility of gastric muscle strips suggesting an indirect action on gastric emptying.
The Biopharmaceutics Classification System (BCS) has found widespread utility in drug discovery, product development and drug product regulatory sciences. The classification scheme captures the two most significant factors influencing oral drug absorption; solubility and intestinal permeability and it has proven to be a very useful and a widely accepted starting point for drug product development and drug product regulation. The mechanistic base of the BCS approach has, no doubt, contributed to its wide spread acceptance and utility. Nevertheless, underneath the simplicity of BCS are many detailed complexities, both in vitro and in vivo which must be evaluated and investigated for any given drug and drug product. In this manuscript we propose a simple extension of the BCS classes to include sub-specification of acid (a), base (b) and neutral (c) for classes II and IV. Sub-classification for Classes I and III (high solubility drugs as currently defined) is generally not needed except perhaps in border line solubility cases. It is well known that the , pKa physical property of a drug (API) has a significant impact on the aqueous solubility dissolution of drug from the drug product both in vitro and in vivo for BCS Class II and IV acids and bases, and is the basis, we propose for a sub-classification extension of the original BCS classification.
In order to develop potent drugs for oral use, information of their pharmacokinetic (PK) properties after oral administration is of great importance. We have recently reported the utility of positron emission tomography (PET) for the analysis of gastrointestinal (GI) absorption of radio labeled compounds. In this study, PET image analysis was performed using novel PET probe, [(18)F]deoxyfluoropoly(ethyleneglycol)s with average molecular weight of 2 kDa ([(18)F]FPEG), as a non-absorbable marker in rat to elaborate on more detail of the GI physiology, such as a segmental transition of the administered water and fluid volume and distribution in the intestine. After oral administration of [(18)F]FPEG solution to rats, a 90-minute PET scan with continuous blood sampling was performed, and then the disposition of radioactivity in each part of GI tract was investigated. Blood PK analysis showed that the bioavailability of [(18)F]FPEG was quite low in rats. PET image analysis showed that the radioactivities after oral administration of [(18)F]FPEG solution were rapidly passed through the stomach, spread into the proximal small intestine, and then transited toward the distal region of the small intestine without decreasing the radioactivities during the GI transition. The radiometabolite analysis revealed that the radioactivities in intestinal mucosal tissues, blood and urine were mainly derived from unchanged [(18)F]FPEG. It was also found that the volume of interests (VOIs) after oral administration of the radiotracer supports to understand the time-dependent manner of effective fluid volume changes in the stomach and the small intestine. In addition, the rate constant of the intestinal transition of radioactivity in each intestinal segment was calculated from the kinetic model analysis, and revealed that PET analysis allows to determine the GI transit from the same individuals and that it is applicable to determine the site specific intestinal absorption. In conclusion, we demonstrated the high potency of PET imaging technique to elucidate the distribution of orally administered solution in the GI tract in vivo.
Purpose:
To evaluate the time-profile of intragastric fluid volume in humans after intragastric administration of drug solution.
Methods:
Eight healthy volunteers were intragastrically administered 150 mL of drug solution containing atenolol (non-absorbable marker) and salicylic acid, then, aliquots of gastric fluid (ca. 2 mL) were sampled for 2 h through the catheter. Rate constants for secretion and emptying of the fluid were obtained by fitting the time-course of atenolol concentration to the simple gastric fluid transit model. Absorption of salicylic acid from the stomach was estimated by comparing its gastric concentration with that of atenolol.
Results:
Kinetic analysis of atenolol concentration in the stomach indicated a rapid emptying of the fluid with an average half-life of 4.2 min. Steady-state intragastric fluid volume in 8 volunteers was estimated as 4-133 mL with an average of 42 mL. Intragastric concentration (normalized by dose) of salicylic acid was always lower than that of atenolol, showing approximately 40% of salicylic acid was absorbed from the stomach before emptying to the intestine.
Conclusions:
This study provided valuable information on intragastric fluid dynamics and gastric drug absorption in humans to establish a better in vitro-in vivo correlation in oral drug absorption.
In vitro dissolution methodologies that adequately capture the oral bioperformance of solid dosage forms are critical tools needed to aid formulation development. Such methodologies must encompass important physiological parameters and be designed with drug properties in mind. Two-phase dissolution apparatuses, which contain an aqueous phase in which the drug dissolves (representing the dissolution/solubility component) and an organic phase into which the drug partitions (representing the absorption component), have the potential to provide meaningful predictions of in vivo oral bioperformance for some BCS II, and possibly some BCS IV drug products. Before such an apparatus can be evaluated properly, it is important to understand the kinetics of drug substance partitioning from the aqueous to the organic medium. A mass transport analysis was performed of the kinetics of partitioning of drug substance solutions from the aqueous to the organic phase of a two-phase dissolution apparatus. Major assumptions include pseudo-steady-state conditions, a dilute aqueous solution and diffusion-controlled transport. Input parameters can be measured or estimated a priori. This paper presents the theory and derivation of our analysis, compares it with a recent kinetic approach, and demonstrates its effectiveness in predicting in vitro partitioning profiles of three BCS II weak acids in four different in vitro two-phase dissolution apparatuses. Very importantly, the paper discusses how a two-phase apparatus can be scaled to reflect in vivo absorption kinetics and for which drug substances the two-phase dissolution systems may be appropriate tools for measuring oral bioperformance. Copyright © 2012 John Wiley & Sons, Ltd.
Echo-planar imaging (EPI) can be used to produce snapshot images of the human stomach and antro-pyloro-duodenal segment in real time as an alternative technique to intubation and exposure to ionizing radiation. The method has been further developed to monitor simultaneous gastric motility and gastric emptying of liquid and solid meals. The model has been utilized to study the effects of pharmacological agents on gastric function.Eight normal subjects were imaged in a 0.5-T superconducting magnet for up to 6 h following ingestion of 800 ml tap water, followed by 500 ml porridge test meal + 500 ml tap water. A rapid multislice technique was adopted to image adjacent transverse slices (10 mm thick) through the gastric region. In addition, three subjects were orally dosed with 20 mg of the prokinetic agent Cisapride. Gastric volumes for each slice were calculated and summed to produce a measure of total gastric volume and gastric emptying. Contractile activity at the level of the antro-pyloric segment was detected using sequential 128 ms images at 3 s intervals. Alternate measurements of gastric volume and motility were made for the duration of the study.Gastric emptyingT
1/2's (times to empty 50% of the gastric contents) of 12.9 min for water and 116 min for porridge were in agreement with results obtained by the traditional techniques of gamma scintigraphy and impedance imaging. The frequency of gastric contractions increased from 2.4 contractions per minute (cpm) to 3.2 cpm following water and from 2.9 to 3.2 cpm following porridge. The prokinetic effect of enhanced coordination of antroduodenal contractions was also observed. These studies have demonstrated that EPI can be used to detect and image gastroduodenal function in man, totally noninvasively, and can be used to study the effects of drugs acting on the gastrointestinal tract.
Loperamide (LOP) is an anti-diarrhoeal agent which is thought to act largely by slowing transit with an uncertain effect on the fluid content of the small and large bowel in humans. Adding simethicone (SIM) to LOP improves its efficacy, but the mechanism of interaction is unclear. Novel MRI techniques to assess small bowel water content (SBWC) have shown that mannitol solutions markedly increase SBWC and can be used as a model of diarrhoea.
We aimed to use quantitative MRI techniques to compare the actions in the gut of LOP and LOP + SIM in a model of secretory diarrhoea using mannitol.
A total of 18 healthy volunteers ingested capsules containing placebo (PLA) or 12 mg LOP or 12 mg LOP + 125 mg SIM. After 100 min they were given a drink containing 5% mannitol in 350 mL of water. They underwent baseline fasting and postprandial serial MRI scans at 45 min intervals for 4.5 h after ingesting the drink. A range of MRI sequences was acquired to image the gut.
LOP and LOP + SIM significantly accelerated gastric emptying (P < 0.03) and reduced SBWC during the late phase (135-270 min after mannitol ingestion), P < 0.009, while delaying arrival of fluid in the ascending colon (AC). The relaxation time T2 of the contents of the AC was reduced by both drugs (P < 0.0001).
LOP and LOP + SIM accelerate gastric emptying, but reduce small bowel water content which may contribute to the delay in oral-caecal transit and overall anti-diarrhoeal effect.
Magnetic resonance (MR) imaging provides direct, non-invasive measurements of gastric function and emptying. The inter-observer variability (IOV) of MR volume measurements and the most appropriate analysis of MR data have not been established. To assess IOV of total gastric volume (TGV) and gastric content volume (GCV) measurements from MR images and the ability of standard power exponential (PowExp), and a novel linear exponential (LinExp) model to describe MR data.
Ten healthy volunteers received three different volumes of a liquid nutrient test meal (200-800 mL) on 3 days in a randomized order. Magnetic resonance scans were acquired using a 1.5T system every 1-5 min for 60 min. Total gastric volume and GCV were measured independently by three observers. Volume data were fitted by PowExp and LinExp models to assess postprandial volume change and gastric emptying half time (T(50) ).
An initial rise in GCV and TGV was often observed after meal ingestion, thereafter GCV and TGV decreased in an approximately linear fashion. Inter-observer variability decreased with greater volumes from 12% at 200 mL to 6% at 600 and 800 mL. Inter-observer variability for T(50) was <5%. PowExp and LinExp models provided comparable estimates of T(50) ; however, only LinExp described dynamic volume change in the early postprandial period.
Gastric MR provides quantitative measurements of postprandial volume change with low IOV, unless the stomach is nearly empty. The novel LinExp model describes the dynamic volume changes in the early postprandial period more accurately than the PowExp model used in existing gastric emptying studies.
Intragastric distribution of solids and liquids is far from uniform but until recently technical limitations have prevented detailed study. Echo planar imaging (EPI), which can provide high-quality images of intragastric contents, has been used in this study to assess the intragastric distribution of oil and water and gastric emptying in subjects lying on either their left or right side. Eight healthy volunteers underwent four gastric emptying studies after consuming either an aqueous meal (400 mL beef consomme soup + 100 mL water) or a fat/aqueous meal (400 mL soup + 100 mL olive oil) lying on either their left or right side.
Using a water suppressed imaging mode the lipid phase was clearly seen layering above the aqueous phase with little evidence of mixing. Gastric emptying of the aqueous meal (A) was not significantly different when lying on the left compared to the right side. However, gastric emptying of the aqueous phase of the fat/aqueous meal (B) was considerably slower when lying on the left compared to the right side, gastric volumes actually increasing over the 90 min of the study P ≤ 0.05. When lying on the right side the aqueous phase of meal B emptied significantly slower than meal A. Oil was clearly observed to layer above the water and fill the duodenal cap when subjects lay on their left and the fundus when they lay on their right side.
EPI clearly demonstrates the intragastric layering of oil which causes posture to strongly influence gastric emptying. EPI is a tool with great potential to describe the intragastric events following ingestion of complex multiphase meals.
To evaluate precipitation in and supersaturation of intestinal contents after administration of pharmacologically relevant doses of dipyridamole and ketoconazole to 12 healthy adults.
On two separate days each subject was administered in stomach 240 ml aqueous solutions of two dipyridamole doses (30/90 mg) and two ketoconazole doses (100/300 mg). Physicochemical characteristics, total drug content, and drug concentration were measured in individual intestinal contents (≤7 ml) aspirated at specific times post-dosing. Drug concentration after incubation (37°C/48 h) and equilibrium solubility were measured. Precipitate crystallinity was evaluated by x-ray powder diffraction.
Precipitated fraction was minimal (dipyridamole, ≤7%) or limited (ketoconazole, ≤16%). Ketoconazole precipitates were mostly amorphous. Depending on dose, intestinal contents with pH > 3.6 were supersaturated with dipyridamole up to 10 and 30 min and with ketoconazole up to 30 and 50 min post-administration. Intestinal contents with pH > 5 and concentration of micellar components <5 mM were supersaturated with ketoconazole or dipyridamole, but precipitated fraction was significant only for ketoconazole. After incubation, crystalline precipitates were found in almost all samples. Slow precipitation of base and/or precipitation of other phases account for this observation.
Intralumenal precipitation of weakly alkaline, lipophilic, high permeability drugs may not be substantial. Estimating intestinal supersaturation in regard to free base is inadequate as other phases may precipitate.
Background Magnetic resonance imaging (MRI) is a useful technique for evaluating gastrointestinal (GI) motor functions because it provides multi-planar imaging capability, high imaging speed, good spatial resolution and excellent soft tissue contrast. Moreover, multiple parameters of GI function can be assessed non-invasively during a single study.
Purpose This critical review of the literature discusses the strengths and limitations of MRI for evaluating GI motor functions.
Pharmaceutical solid oral dosage forms must undergo dissolution in the intestinal fluids of the gastrointestinal tract before they can be absorbed and reach the systemic circulation. Therefore, dissolution is a critical part of the drug-delivery process. The rate and extent of drug dissolution and absorption depend on the characteristics of the active ingredient as well as properties of the dosage form. Just as importantly, characteristics of the physiological environment such as buffer species, pH, bile salts, gastric emptying rate, intestinal motility, and hydrodynamics can significantly impact dissolution and absorption. While significant progress has been made since 1970 when the first compendial dissolution test was introduced (USP apparatus 1), current dissolution testing does not take full advantage of the extensive physiologic information that is available. For quality control purposes, where the question is one of lot-to-lot consistency in performance, using nonphysiologic test conditions that match drug and dosage form properties with practical dissolution media and apparatus may be appropriate. However, where in vitro-in vivo correlations are desired, it is logical to consider and utilize knowledge of the in vivo condition. This publication critically reviews the literature that is relevant to oral human drug delivery. Physiologically relevant information must serve as a basis for the design of dissolution test methods and systems that are more representative of the human condition. As in vitro methods advance in their physiological relevance, better in vitro-in vivo correlations will be possible. This will, in turn, lead to in vitro systems that can be utilized to more effectively design dosage forms that have improved and more consistent oral bioperformance.
The FDA classifies a drug substance as high-permeability when the fraction of dose absorbed (F(abs)) in humans is 90% or higher. This direct correlation between human permeability and F(abs) has been recently controversial, since the beta-blocker sotalol showed high F(abs) (90%) and low Caco-2 permeability. The purpose of this study was to investigate the scientific basis for this disparity between permeability and F(abs). The effective permeabilities (P(eff)) of sotalol and metoprolol, a FDA standard for the low/high P(eff) class boundary, were investigated in the rat perfusion model, in three different intestinal segments with pHs corresponding to the physiological pH in each region: (1) proximal jejunum, pH 6.5; (2) mid small intestine, pH 7.0; and (3) distal ileum, pH 7.5. Both metoprolol and sotalol showed pH-dependent permeability, with higher P(eff) at higher pH. At any given pH, sotalol showed lower permeability than metoprolol; however, the permeability of sotalol determined at pH 7.5 exceeded/matched metoprolol's at pH 6.5 and 7.0, respectively. Physicochemical analysis based on ionization, pK(a) and partitioning of these drugs predicted the same trend and clarified the mechanism behind these observed results. Experimental octanol-buffer partitioning experiments confirmed the theoretical curves. An oral dose of metoprolol has been reported to be completely absorbed in the upper small intestine; it follows, hence, that metoprolol's P(eff) value at pH 7.5 is not likely physiologically relevant for an immediate release dosage form, and the permeability at pH 6.5 represents the actual relevant value for the low/high permeability class boundary. Although sotalol's permeability is low at pH 6.5 and 7.0, at pH 7.5 it exceeds/matches the threshold of metoprolol at pH 6.5 and 7.0, most likely responsible for its high F(abs). In conclusion, we have shown that, in fact, there is no discrepancy between P(eff) and F(abs) in sotalol's absorption; the data emphasize that, if a compound has high fraction of dose absorbed, it will have high-permeability, not necessarily in the jejunum, but at some point along the relevant intestinal regions.
5-HT(3) antagonists have been shown to be effective in relieving the symptoms of irritable bowel syndrome with diarrhoea (IBS-D). Using a recently validated magnetic resonance imaging (MRI) method, we have demonstrated reduced fasting small bowel water content (SBWC) in IBS-D associated with accelerated small bowel transit. We hypothesized that slowing of transit with ondansetron would lead to an increase in SBWC by inhibiting fasting motility.
To assess the effects of ondansetron compared with placebo in healthy volunteers on SBWC and motility in two different groups of subjects, one studied using MRI and another using manometry.
Healthy volunteers were given either a placebo or ondansetron on the day prior to and on the study day. Sixteen volunteers underwent baseline fasting and postprandial MRI scans for 270 min. In a second study, a separate group of n = 18 volunteers were intubated and overnight migrating motor complex (MMC) recorded. Baseline MRI scans were carried out after the tube was removed.
Fasting SBWC was markedly increased by ondansetron (P < 0.0007). Ondansetron reduced the overall antroduodenal Motility Index (P < 0.04). The subjects who were intubated had significantly lower fasting SBWC (P < 0.0002) compared with the group of subjects who were not intubated.
The 5-HT(3) receptor antagonism increased fasting small bowel water. This was associated with reduced fasting antroduodenal Motility Index which may explain the clinical benefit of such drugs.
Postprandial symptoms are common in patients with irritable bowel syndrome with diarrhea (IBS-D) and could be diet related. We studied postprandial changes in distribution of water in the upper gastrointestinal tract of healthy volunteers (HVs) and patients with IBS-D after contrasting meals.
In study 1, 11 HVs consumed 350-mL test meals with 5% mannitol (unabsorbable) or 5% glucose (readily absorbed). In study 2, 17 HVs consumed a 331-kcal meal, with or without 15 g bran. In study 3, 26 patients with IBS-D consumed the study 2 diet with bran meal. All subjects underwent serial magnetic resonance imaging analysis.
In study 1, subjects' small bowel water content (SBWC) increased after the mannitol but not glucose meals, reaching 381 mL (interquartile range, 343-491 mL) and 47 mL (18-78 mL), respectively, 40 minutes after eating (P < .001). In study 2, SBWC initially decreased after both meal types and then increased, plateauing at 180-405 minutes and was greater after the bran meal (P = .02). In study 3, fasting and postprandial SBWC was lower in IBS-D than in HVs (P < .05 and P < .0001, respectively). Patients with IBS-D had faster orocecal transit times (135 minutes; 90-180 minutes) compared with HVs (225 minutes; 203-293 minutes; P < .0001) and reduced terminal ileum diameter (P < .003).
Postprandial SBWC initially decreases, because of rapid, nutrient-driven fluid absorption, and then increases after a mixed liquid/solid meal. Patients with IBS-D have reduced fasting and postprandial SBWC with faster transit, possibly indicating increased small intestinal tone.
Water volume has impact when the compound has low aqueous solubility. For example, the absorption of compounds with a Biopharmaceutics Classification System class 2 or 4 is likely to be solubility-limited. Provided the formulation does not contribute to a dissolution-limited condition (e.g., particle size, Waterman and Sutton, J Control Release 86:293-304, 2003) and permeability is rapid, any impact on solubility factors in the gastrointestinal (GI) tract will directly impact the fraction absorbed These factors are in situ solubility, precipitation, and volume of water. Using GastroPlus, models were developed with literature values of water volume in the small (SIWV) and large (LIWV) intestines for several solubility limited compounds. One or more models were developed for the mean plasma concentration-time profile of each compound. The consistency of the models with known literature and experimental data for the compounds' solubility and precipitation was determined. The SIWV associated with best fits of solubility limited compounds averaged about 130 ml, with a range of 10-150 ml in the fasted state. The average LIWV in the fasted state was about 10 ml and ranged as large as 125 ml. The wide range of individual LIWV values is likely due to variability in pharmacokinetics, permeability, GI transit, and the observation that data set was collected during a "snapshot in time". The preferred values of 10% organ volume for small intestine and 1-10% organ volume for large intestine are recommended in lieu of the GastroPlus default values of 40% and 10%, respectively.
International guidelines allow healthy patients to drink clear liquid up to 2 h before general anesthesia. Recently, MRI measurements have been used for tracking gastric volume in humans. Hence, we used MRI to examine the gastric emptying rate of water in healthy volunteers with or without prior water loading.
Fifteen healthy volunteers were enrolled. The participants had MRI examinations on separate days under two different protocols: The preliminary hydration protocol (group H) and the water restriction protocol (group R). After the intake of water, MR imaging was performed every 10 min for 60 min. The gastric content was outlined as area of interest (AOI), and the AOI area of each slice was summated to calculate the volume of gastric contents.
The 50% reduction time of gastric volume in group R and group H was 18+/-9 and 16+/-8 min (mean+/-SD), respectively. There were no significant changes between the two groups.
The gastric emptying time for water evaluated with MRI was not affected by preliminary hydration, which shows the safety of repeated oral hydrations in the pre-operative period.
Test meals consisting of water or a suspension of barium sulphate were given to two normal subjects. The rates of decrease of the volume of the gastric contents were indistinguishable for the two meals.
Gastrointestinal (GI) absorption of the beta-adrenoceptor blocker metoprolol was investigated in five healthy subjects by means of an intubation method, employing a triple-lumen tube introduced into the intestine, and a twin-lumen tube in the stomach. Metoprolol was introduced into the stomach with a homogenized meal containing a nonabsorbable marker, [14C]-PEG 4000, and another marker, PEG 4000, was perfused continuously into the duodenum just below the pylorus. Samples of GI contents were collected at regular intervals over 4 h in the stomach and at two different levels in the upper small intestine. Metoprolol was not absorbed from the stomach. Approximately 60% of the amount of drug emptied from the stomach was absorbed from the duodenum; about 50% of that leaving the duodenum was absorbed from the first part of the jejunum. The delivery process was the rate-limiting factor of metoprolol absorption in these segments of the gut. Plasma concentrations reflected drug loss from the lumen and were higher in subjects exhibiting faster gastric emptying and higher absorption rates in the duodenum and jejunum. The intubation technique appeared to be a suitable method for investigating drug absorption from the GI tract in man.
This study assessed the gastric emptying rates of water and four isocaloric carbohydrate solutions in resting subjects. On five occasions, subjects ingested 400 ml of water or 6% solutions of glucose, sucrose, maltodextrin, and sucrose+glucose. The double-sampling technique was used to sample stomach contents immediately after ingestion and at 10-min intervals until emptying was complete. Comparisons of various criteria of gastric emptying (percentage of initial beverage volume remaining in the stomach, mean gastric emptying rates, and gross gastric volumes) provided somewhat different results. For example, when gastric emptying was portrayed as the percentage of initial beverage volume remaining in the stomach, the glucose and maltodextrin beverages exhibited significantly slower emptying characteristics; there were no differences in this measure among water, sucrose, and sucrose+glucose. Similar results were noted when changes in gross gastric volumes were compared. However, when the results are expressed as mean gastric emptying rates (in ml.min-1), few differences are noted among beverage treatments. Gastric emptying rate was not influenced by the osmolality of the ingested solutions. The results of this study demonstrate the importance of using more than one measurement criteria to assess and compare gastric emptying characteristics.
Current MR meal markers may interfere with gastric motility and secretion restricting the use of MRI in the measurement of gastric physiology. We therefore evaluated Gd-DOTA as a liquid phase marker, in vitro by determining dissociation, and adherence to the solids, and in vivo by simultaneous MRI (0.35 T scanner, multiple T1-weighted sections of the upper abdomen) and double indicator (perfusion marker PEG 4000, meal marker 99mTc-DTPA) measurements of emptying and secretion, following ingestion of 500 ml 10% glucose. In vitro Gd-DOTA was stable at a pH > 2 with < 2% dissociation at 24 h during incubation with HCl. Dissociation during incubation with HCl was linearly dependent on H+ concentration (0.77 < pH < 2.02). Less Gd-DOTA was absorbed onto the solid phase than 99mTc-DTPA (25% cf 36%). In vivo Gd-DOTA marked gastric contents provided strong positive contrast. Similar emptying curves were observed with both MRI and double-indicator techniques (r = 0.987, P < 0.001). Gd-DOTA has the potential to be a useful liquid phase contrast agent in MR studies on gastric function.
Glucagon-like peptide-1 (GLP-1) has been shown to inhibit gastric emptying of a caloric load but the effect on a non-caloric load is unknown.
Seven healthy men were studied after an over-night fast. Thirty min before the intake of 330 ml radioactively labeled water either GLP-1 (0.75 pmol/kg/min) or saline was administered intravenously and continued for 75 min. Scintigraphic gastric emptying was performed for 45 min and plasma samples were obtained for analysis of vasopressin, sodium, osmolality, GLP-1, insulin, and glucose. In addition, electric field stimulation of human gastric muscle strips was done.
The median (range) percent water retained in the stomach, 45 min after intake of water, was 96% (68%-98%) and 12% (2%-42%) (P = 0.02) during infusion of GLP-1 and saline, respectively. Additionally, GLP-1 did not affect basal tone or contractile response of gastric muscle strips to electric field stimulation or acetylcholine (ACh). There was no change in plasma concentrations of vasopressin, sodium, or plasma osmolality during GLP-1 compared to saline infusion.
GLP-1 has a profound inhibitory effect on the gastric emptying of water in man, but no short-term effect on water homeostasis. No effect was seen on contractility of gastric muscle strips suggesting an indirect action on gastric emptying.
The objective of this study was to test various aspects of dissolution media simulating the intralumenal composition of the small intestine, including the suitability of the osmolality-adjusting agents and of the buffers, the substitution of crude sodium taurocholate (from ox bile) for pure sodium taurocholate and the substitution of partially hydrolysed soybean phosphatidylcholine for egg phosphatidylcholine. It was concluded that biorelevant media should contain sodium as the major cation species to better reflect the physiology. However, the use of non-physiologically relevant buffers is inevitable, especially for simulation of the fed state in the small intestine. The buffers used may affect the solubility product of weakly basic compounds with pK(a)(s) higher than about 5, the solubility of extremely highly lipophilic compounds due to salting in/out properties of the anion of the buffer and the stability of the dissolving compound. It is prudent in relevant situations to run an additional dissolution test in a modified fed state simulated intestinal fluid (FeSSIF) (or fasted state simulated intestinal fluid (FaSSIF), where applicable) containing alternative buffer species. Although a mixture of bile salts is physiologically more relevant than pure sodium taurocholate, this issue seems to be of practical importance in only a few cases. Adequate simulations in these cases will probably require the use of a number of pure substances and could substantially increase the cost of the test. Finally, unless the drug is extremely lipophilic (ca. logP> 5), egg phosphatidylcholine can be substituted by partially hydrolysed soybean phosphatidylcholine.
In this study, the importance of accurate simulation of fasting gastric environment for the assessment of the absorption process of two model lipophilic compounds, GR253035X (weak base) and atovaquone (non-ionizable), was assessed. Dissolution profiles were constructed in previously proposed simulated gastric fluids and in a new medium that comprises only of components that have been recovered from the fasting stomach. Dissolution data obtained in a more physiologically relevant medium led to better correlation between the simulated and actual intralumenal dissolution vs. time profiles for GR253035X. In contrast, accurate simulation of gastric environment did not affect the simulated plasma profile of atovaquone. Accurate simulation of the fasting gastric contents may be crucial for the assessment of the absorption profile of lipophilic weak bases.
The gastrointestinal transit of sequentially administered capsules was investigated in relation to the availability of fluid along the intestinal lumen by magnetic resonance imaging.
Water-sensitive magnetic resonance imaging was performed on 12 healthy subjects during fasting and 1 h after a meal. Specifiable non-disintegrating capsules were administered at 7, 4 and 1 h prior to imaging.
While food intake reduced the mean fluid volumes in the small intestine (105 +/- 72 mL vs. 54 +/- 41 mL, P < 0.01) it had no significant effect on the mean fluid volumes in the colon (13 +/- 12 mL vs. 18 +/- 26 mL). The mean number of separated fluid pockets increased in both organs after meal (small intestine: 4 vs. 6, P < 0.05; large intestine: 4 vs. 6, P < 0.05). The distribution of capsules between the small and large intestine was strongly influenced by food (colon: 3 vs. 17 capsules, P < 0.01).
The results show that fluid is not homogeneously distributed along the gut, which likely contributes to the individual variability of drug absorption. Furthermore, transport of fluid and solids through the ileocaecal valve is obviously initiated by a meal-induced gastro-ileocaecal reflex.
This study was conducted to compare the luminal composition of the upper gastrointestinal tract in the fasted and fed states in humans, with a view toward designing in vitro studies to explain/predict food effects on dosage form performance.
Twenty healthy human subjects received 250 mL water or 500 mL Ensure plus (a complete nutrient drink) through a nasogastric tube and samples were aspirated from the gastric antrum or duodenum for a period up to 3.5 h, depending on location/fluid combination. Samples were analyzed for polyethylene glycol, pH, buffer capacity, osmolality, surface tension, pepsin, total carbohydrates, total protein content, and bile salts.
Following Ensure plus administration, gastric pH was elevated, buffer capacity ranged from 14 to 28 mmoL L-1 DeltapH-1 (vs. 7-18 mmol L-1 DeltapH-1), contents were hyperosmolar, gastric pepsin levels doubled, and surface tension was 30% lower than after administration of water. Post- and preprandial duodenal pH values were initially similar, but slowly decreased to 5.2 postprandially, whereas buffer capacity increased from 5.6 mmol L-1 DeltapH-1 (fasted) to 18-30 mmol L-1 DeltapH-1 (p<0.05). Postprandial surface tension in the duodenum decreased by >30%, bile salt levels were two to four times higher, luminal contents were hyperosmotic, and the presence of peptides and sugars was confirmed.
This work shows that, in addition to already well characterized parameters (e.g., pH, and bile salt levels), significant differences in buffer capacity, surface tension, osmolality, and food components are observed pre-/postprandially. These differences should be reflected in test media to predict food effects on intralumenal performance of dosage forms.
The in vitro dissolution of carbamazepine (CBZ) was investigated using an automated artificial stomach-duodenum (ASD) model. Successful simulation of the dog physiology in the fasted state showed that the rank order of the ASD estimated bioavailabilities is as follows: Form III > Form I > dihydrate. This result is in excellent agreement with those found in literature. Additional simulations comparing different gastric transit times during fasted and fed states are also discussed. (c) 2005 Wiley-Liss, Inc.
Solubilities measured in water are not always indicative of solubilities in the gastrointestinal tract. The use of aqueous solubility to predict oral drug absorption can therefore lead to very pronounced underestimates of the oral bioavailability, particularly for drugs which are poorly soluble and lipophilic. Mechanisms responsible for enhancing the luminal solubility of such drugs are discussed. Various methods for estimating intra-lumenal solubilities are presented, with emphasis on the two most widely implemented methods: determining solubility in fluids aspirated from the human gastrointestinal tract, and determining solubility in so-called biorelevant media, composed to simulate these fluids. The ability of the biorelevant media to predict solubility in human aspirates and to predict plasma profiles is illustrated with case examples.
Substantial water fluxes across the small intestine occur during digestion of food, but so far measuring these has required invasive intubation techniques. This paper describes a non-invasive magnetic resonance imaging (MRI) technique for measuring small bowel water content which has been validated using naso-duodenal infusion. Eighteen healthy volunteers were intubated, with the tube position being verified by MRI. After a baseline MRI scan, each volunteer had eight 40 ml boluses of a non-absorbable mannitol and saline solution infused into their proximal small bowel with an MRI scan being acquired after each bolus. The MRI sequence used was an adapted magnetic resonance cholangiopancreatography sequence. The image data were thresholded to allow for intra- and inter-subject signal variations. The MRI measured volumes were then compared to the known infused volumes. This MRI technique gave excellent images of the small bowel, which closely resemble those obtained using conventional radiology with barium contrast. The mean difference between the measured MRI volumes and infused volumes was 2% with a standard deviation of 10%. The maximum 95% limits of agreement between observers were -15% to +17% while measurements by the same operator on separate occasions differed by only 4%. This new technique can now be applied to study alterations in small bowel fluid absorption and secretion due to gastrointestinal disease or drug intervention.
The design of a proper region-specific oral drug delivery system has to take into consideration the differences in anatomy, physiology and absorption characteristics that exist between segments within the gastrointestinal (GI) tract, as well as transit kinetics of the dosage form and the site of drug release within the GI tract.
The aim of this review is to examine the various biopharmaceutical aspects of region-specific drug delivery in the GI tract.
This review is mainly focused on pharmacokinetic and pharmacodynamic aspects of region-selective drug delivery with special emphasis on drug absorption pathways (para- and transcellular, absorption and efflux transporters, lymphatic uptake etc.). It includes a discussion of gastroretentive systems, colonic delivery, and lipid-based formulations. The review also addresses targeted therapy of local diseases within the GI tract.
The advances in pharmaceutical technology allow for the development of a variety of region-specific drug delivery systems for oral administration to optimize local and systemic therapy.
Guidance for industry: food-effect bioavailability and fed bioequivalence studies. U.S. Department of Health and Human Services
- Fda
FDA. Guidance for industry: food-effect bioavailability and fed
bioequivalence studies. U.S. Department of Health and Human
Services, Centre for Drug Evaluation and Research (CDER), 2002.
Effects of an osmotic laxative on the distribution of water between the small and large intestine in humans
- E Placidi
- C L Hoad
- L Marciani
- P A Gowland
- R C Spiller
Placidi, E.; Hoad, C. L.; Marciani, L.; Gowland, P. A.; Spiller, R. C. Effects of an osmotic laxative on the distribution of water between the small and large intestine in humans. Gut 2010, 59 (S1), A141.
Gastric emptying of barium sulfate suspension compared with that of water Effect of the preliminary hydration on gastric emptying time for water in healthy volunteers GLP-1 inhibits gastric emptying of water but does not influence plasma vasopressin, sodium, or osmolality
- M T Knox
- J N Hunt
- T Umenai
- N Arai
- E Chihara
Knox, M. T.; Hunt, J. N. Gastric emptying of barium sulfate suspension compared with that of water. Gut 1977, 18, 541−2. (10) Umenai, T.; Arai, N.; Chihara, E. Effect of the preliminary hydration on gastric emptying time for water in healthy volunteers. Acta Anaesthesiol. Scand. 2009, 53, 223−6. (11) Naslund, E.; Bogefors, J.; Gryback, P.; Bjellerup, P.; Jacobsson, H.; Holst, J. J.; Hellstrom, P. M. GLP-1 inhibits gastric emptying of water but does not influence plasma vasopressin, sodium, or osmolality. Scand. J. Gastroenterol. 2001, 36, 156−62.
Mechanistic analysis of solute transport in an in vitro physiological two-phase dissolution apparatus 378−402. (40) Deloose, E.; Janssen, P.; Depoortere, I.; Tack, J. The migrating motor complex: control mechanisms and its role in health and disease
- G E Amidon
Amidon, G. E. Mechanistic analysis of solute transport in an in vitro physiological two-phase dissolution apparatus. Biopharm. Drug Dispos. 2012, 33, 378−402. (40) Deloose, E.; Janssen, P.; Depoortere, I.; Tack, J. The migrating motor complex: control mechanisms and its role in health and disease. Nat. Rev. Gastroenterol. Hepatol. 2012, 9, 271−85. (41) Dahan, A.; Miller, J. M.; Hilfinger, J. M.; Yamashita, S.; Yu, L. X.;
Relative bioavailability estimation of carbamazepine crystal forms using an artificial stomach-duodenum model The biopharmaceutics classification system: subclasses for in vivo predictive dissolution (IPD) methodology and IVIVC. Eur
- M D M Hawley
- P Langguth
- G E Amidon
- G L Amidon
- G L Amidon
Hawley, M. Relative bioavailability estimation of carbamazepine crystal forms using an artificial stomach-duodenum model. J. Pharm. Sci. 2006, 95, 116−25. (38) Tsume, Y.; Mudie, D. M.; Langguth, P.; Amidon, G. E.; Amidon, G. L. The biopharmaceutics classification system: subclasses for in vivo predictive dissolution (IPD) methodology and IVIVC. Eur. J. Pharm. Sci. 2014, 57, 152−63. (39) Mudie, D. M.; Shi, Y.; Ping, H.; Gao, P.; Amidon, G. L.;
Molecular Pharmaceutics Article dx.doi.org/10.1021/mp500210c | Mol
- M Kataoka
- D Ozaki
- H Doi
- M Suzuki
- S Ishida
- S Yamashita
Kataoka, M.; Ozaki, D.; Doi, H.; Suzuki, M.; Ishida, S.; Molecular Pharmaceutics Article dx.doi.org/10.1021/mp500210c | Mol. Pharmaceutics 2014, 11, 3039−3047 Hatanaka, K.; Sugiyama, Y.; Akai, S.; Oku, N.; Yamashita, S.;
Noninvasive quantification of small bowel water content by MRI: a validation study Validation of a novel, noninvasive assessment of gastric function and gastric emptying (GE) after a large liquid nutrient meal by magnetic resonance imaging (MRI)
- D Bush
- E F Cox
- E Campbell
- R C Spiller
- P A Gowland
Bush, D.; Cox, E. F.; Campbell, E.; Spiller, R. C.; Gowland, P. A. Noninvasive quantification of small bowel water content by MRI: a
validation study. Phys. Med. Biol. 2007, 52, 6909−22.
(26) Parker, H. L.; Hoad, C. L.; Hudders, N.; Costigan, C.; Marciani,
L.; Cox, E.; Gowland, P. A.; Fox, M. R. Validation of a novel, noninvasive assessment of gastric function and gastric emptying (GE) after
a large liquid nutrient meal by magnetic resonance imaging (MRI).
Mechanistic analysis of solute transport in an in vitro physiological two-phase dissolution apparatus Depoortere, I.; Tack, J. The migrating motor complex: control mechanisms and its role in health and disease
- G Amidon
- E Deloose
- P Janssen
Amidon, G. E. Mechanistic analysis of solute transport in an in vitro
physiological two-phase dissolution apparatus. Biopharm. Drug Dispos.
2012, 33, 378−402.
(40) Deloose, E.; Janssen, P.; Depoortere, I.; Tack, J. The migrating
motor complex: control mechanisms and its role in health and disease.
Nat. Rev. Gastroenterol. Hepatol. 2012, 9, 271−85.
(41) Dahan, A.; Miller, J. M.; Hilfinger, J. M.; Yamashita, S.; Yu, L. X.;
The effects of loperamide, or loperamide plus simethicone, on the distribution of gut water as assessed by MRI in a mannitol model of secretory diarrhoea Characterization of the human upper gastrointestinal contents under conditions simulating bioavailability/ bioequivalence studies
- A Kalantzi
- L Goumas
- K Kalioras
- V Abrahamsson
- B Dressman
- J B Reppas
A. The effects of loperamide, or loperamide plus simethicone, on the
distribution of gut water as assessed by MRI in a mannitol model of
secretory diarrhoea. Aliment. Pharmacol. Ther. 2012, 36, 64−73.
(31) Kalantzi, L.; Goumas, K.; Kalioras, V.; Abrahamsson, B.;
Dressman, J. B.; Reppas, C. Characterization of the human upper
gastrointestinal contents under conditions simulating bioavailability/
bioequivalence studies. Pharm. Res. 2006, 23, 165−76.
(32) Vertzoni, M.; Fotaki, N.; Kostewicz, E.; Stippler, E.; Leuner, C.;
GLP-1 inhibits gastric emptying of water but does not influence plasma vasopressin, sodium, or osmolality Gastric emptying of water and isocaloric carbohydrate solutions consumed at rest The measurement of gastric motor function and transit in man by echo planar magnetic resonance imaging
- Acta Anaesthesiol
- E Scand Naslund
- J Bogefors
- P Gryback
- P Bjellerup
- H Jacobsson
- J J Holst
- P M Hellstrom
- R Murray
- D E Eddy
- W P Bartoli
- G L Paul
- V Adams
- J Hykin
- P R Gowland
- P Mansfield
Acta Anaesthesiol. Scand. 2009, 53, 223−6.
(11) Naslund, E.; Bogefors, J.; Gryback, P.; Bjellerup, P.; Jacobsson,
H.; Holst, J. J.; Hellstrom, P. M. GLP-1 inhibits gastric emptying of
water but does not influence plasma vasopressin, sodium, or
osmolality. Scand. J. Gastroenterol. 2001, 36, 156−62.
(12) Murray, R.; Eddy, D. E.; Bartoli, W. P.; Paul, G. L. Gastric
emptying of water and isocaloric carbohydrate solutions consumed at
rest. Med. Sci. Sports Exercise 1994, 26, 725−32.
(13) Wright, J.; Adams, V.; Hykin, J.; Gowland, P.; Issa, B.; Boulby,
P.; Tokarczuk, P.; Evans, D.; Spiller, R.; Mansfield, P. The
measurement of gastric motor function and transit in man by echo
planar magnetic resonance imaging. Magn. Reson. Mater. Phys. 1994, 2,
467−9.
(14) Steingoetter, A.; Fox, M.; Treier, R.; Weishaupt, D.; Marincek,
B.; Boesiger, P.; Fried, M.; Schwizer, W. Effects of posture on the
physiology of gastric emptying: A magnetic resonance imaging study.
- T Shingaki
- T Takashima
- Wada
Aliment. Pharmacol. Ther. 2005, 22, 971−9.
(16) Shingaki, T.; Takashima, T.; Wada, Y.; Tanaka, M.; Kataoka, M.;