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Intestinal Epithelium and Drug Transporters

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Abstract

This chapter focuses on factors influencing regional epithelial permeation of drugs related especially to transporters. It highlights the important key messages as regard to modified‐release formulations. Drug absorption for ionizable drugs is determined by the pH in the region of intended release. Uptake and efflux transporters expressed in the gastrointestinal tract modulate the absorption of several drugs. Uptake transporters are more likely to act in synergy with other enzymes whose regional distribution is similar to CYP3A4, such as glucuronosyltransferases, sulfotransferases, and glutathione‐S‐transferases. The impact of the interplay between drug transport and metabolism on regional absorption can also be studied with perfusion techniques using cannulated in situ or isolated ex vivo intestinal regions in the rat. Drug–drug interactions can lead to changed systemic exposure, resulting in variations in drug response of the coadministered drug/s as well as safety concerns especially for low therapeutic index drugs.

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In recent years, an increasing number of clinical drug-drug interactions (DDIs) have been attributed to inhibition of intestinal organic anion transporting polypeptides (OATPs); however, only a few of these DDI results were reflected in drug labels. This review aims to provide a thorough analysis of intestinal OATP-mediated pharmacokinetic-based DDIs, using both in vitro and clinical investigations, highlighting the main mechanistic findings and discussing their clinical relevance. On the basis of pharmacogenetic and clinical DDI results, a total of 12 drugs were identified as possible clinical substrates of OATP2B1 and/or OATP1A2. Among them, three drugs, namely atenolol, celiprolol, and fexofenadine have emerged as the most sensitive substrates to evaluate clinical OATP-mediated intestinal DDIs when interactions with P-glycoprotein (P-gp) by the test compound can be ruled out. With regard to perpetrators, eight dietary or natural products and one investigational drug, ronacaleret (now terminated), showed clinical intestinal inhibition attributable to OATPs, producing ≥ 20% decreases in AUC of the co-administered drug. Common juices such as apple juice, grapefruit juice, and orange juice are considered potent inhibitors of intestinal OATP2B1 and/or OATP1A2 (decreasing exposure of the co-administered substrate by approximately 85%), and may be adequate prototype inhibitors to investigate intestinal DDIs mediated by OATPs.
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Orally administered drugs must pass through the intestinal wall and then through the liver before reaching systemic circulation. During this process drugs are subjected to different processes that may determine the therapeutic value. The intestinal barrier with active drug metabolizing enzymes and drug transporters in enterocytes plays an important role in the determination of drug bioavailability. Accumulating information demonstrates variable distribution of drug metabolizing enzymes and transporters along the human gastrointestinal tract (GI), that creates specific barrier characteristics in different segments of the GI. In this review, expression of drug metabolizing enzymes and transporters in the healthy and diseased human GI as well as their regulatory aspects: genetic, miRNA, DNA methylation are outlined. The knowledge of unique interplay between drug metabolizing enzymes and transporters in specific segments of the GI tract allows more precise definition of drug release sites within the GI in order to assure more complete bioavailability and prediction of drug interactions.
Article
Although oral drug administration is nowadays the favourable route of administration, intestinal drug absorption is challenged by several highly variable and poorly predictable processes such as gastrointestinal motility, intestinal drug solubility and intestinal metabolism. One further determinant that have been identified and characterized during the last two decades is the intestinal drug transport that is mediated by several transmembrane proteins such as P-gp, BCRP, PEPT1 and OATP2B1. It is so far well-established that intestinal transporters can affect oral absorption of many drugs in a significant manner either by facilitating their cellular uptake or by pumping them back to gut lumen which limits their oral bioavailability. Their functional relevance becomes even more apparent in cases of unwanted drug-drug interactions when concomitantly given drugs cause transporter induction or inhibition which in turn leads to increased or decreased drug exposure. The longitudinal expression of several intestinal transporters is not homogeneous along the human intestine which may has functional implications on the preferable site of intestinal drug absorption. Besides the knowledge about the expression of pharmacologically relevant transporters in human intestinal tissue, also their exact localization on the apical or basolateral membrane of enterocytes is of interest but in several cases debatable. Finally, there is obviously a coordinative interplay of intestinal transporters (apical - basolateral), intestinal enzymes and transporter as well as intestinal and hepatic transporters. This review aims to give an updated overview about the expression, localization, regulation and function of clinically relevant transporter proteins in the human intestine.
Article
Although carnitine is present in a variety of foods, the mechanism of its absorption has not been previously studied in humans. We investigated the absorption of carnitine by studying uptake into human intestinal mucosal biopsy specimens. We found evidence of active transport in the duodenum and ileum, but not in the colon. We demonstrated that intracellular concentrations exceeded concentrations in the incubation media at steady states and that uptake against a concentration gradient was abolished by anoxia and by replacement of sodium ion with potassium. Studies of initial rate of uptake over a range of concentrations revealed a curve consistent with a two-component system: a saturable system with a kt of 558 μM and a linear component probably representing passive diffusion. Addition of d-carnitine and l-acetylcarnitine resulted in diminished uptake of l-carnitine, suggesting that these substrates utilize the same transport mechanism. These studies demonstrate the presence of an active intestinal transport system for l-carnitine in human intestinal mucosa.
Article
Over the last 5 years the quantification of transporter protein absolute abundances has dramatically increased in parallel to the expanded use of in vitro - in vivo extrapolation (IVIVE) and physiologically-based pharmacokinetics (PBPK) linked models, for decision making in pharmaceutical company drug development pipelines and regulatory submissions. Although several research groups have developed laboratory-specific proteomic workflows, it is unclear if the large range of reported variability is founded on true inter-individual variability or experimental variability, due to sample preparation, or the proteomic methodology used. To assess the potential for methodological bias on end-point abundance quantification, two independent laboratories, the University of Manchester (UoM) and Bertin Pharma (BPh), employing different proteomic workflows, quantified the absolute abundances of Na/K-ATPase, P-gp and BCRP in the same set of biological samples from human intestinal and Caco-2 cell membranes. Across all samples, P-gp abundances were significantly correlated (p = 0.04, rs = 0.72) with a 2.4-fold higher abundance (p = 0.001) generated at the UoM compared to BPh. There was a systematically higher BCRP abundance in Caco-2 cell samples quantified by BPh compared to UoM, but not in human intestinal samples. Consequently, a similar intestinal relative expression factor (REF), based on distal jejunum and Caco-2 monolayer samples, between laboratories was found for P-gp. However, a 2-fold higher intestinal REF was generated by the UoM (2.22) versus BPh (1.11). We demonstrate that differences in absolute protein abundance are evident between laboratories and those are likely to be founded on laboratory-specific methodologies relating to peptide choice.
Article
The aim of the present study was to investigate the influence of molecular mass and thiol group content of poly(acrylic acid)-cysteine conjugates on the permeation of sulforhodamine 101 and penicillin G. acting as substrates for multidrug resistance-associated protein 2 efflux pump. Poly(acrylic acids) of 2 kDa, 100 kDa, 250 kDa, 450 kDa and 3000 kDa were conjugated with cysteine. The thiol group content of all these polymers was in the range of 343.3±48.4μmol/g to 450.3±76.1μmol/g. Transport studies were performed on rat small intestine mounted in Ussing-type chambers. Since 250 kDa poly(acrylic acid) showed the highest permeation enhancing effect, additionally thiolated 250 kDa polyacrylates displaying 157.2μmol/g, 223.0±18.1 and 355.9μmol/g thiol groups were synthesized in order to investigate the influence of thiol group content on the permeation enhancement. The permeation of sulforhodamine was 3.93- and 3.85- fold improved using 250 kDa poly(acrylic acid)-cysteine conjugate exhibiting 355.9±39.5μmol/g and 223.0±18.1μmol/g thiol groups. Using the same conjugates the permeation of penicilin G was 1.70- and 1.59- fold improved, respectively. The study demonstrates that thiolated poly(acrylic acid) inhibits Mrp2 mediated transport and that the extent of inhibition depends on the molecular mass and degree of thiolation of the polymer. Copyright © 2015 Elsevier B.V. All rights reserved.
Article
Introduction: The incidence of pediatric celiac disease has risen and many of these children will receive medications at some time in their life. However, the absorption of drugs in pediatric patients with celiac disease has never been studied. The few studies that do exist have only been performed in adults and indicate that drug concentrations can be altered for some drugs. It is also noteworthy that few researchers have conducted studies to determine if the distribution, metabolism, and excretion of drugs are altered in celiac disease. Areas covered: The pharmacokinetics of drugs greatly differ between children and adults. Combined with the pathophysiological changes known to occur with celiac disease, there is compelling evidence to support that drug exposure in pediatric celiac disease may be altered. Relevant characteristics of celiac disease that may affect drug disposition include intestinal atrophy, hypoalbuminemia, reduced CYP3A enzymes, and thyroid dysfunction. Expert opinion: The safety and efficacy of drug dosing in children with celiac disease can be enhanced with additional pharmacokinetic studies of commonly prescribed drugs in this population. Ideally, these studies should include drugs that have high bioavailability, are highly protein bound, undergo extensive CYP3A enzyme metabolism, and/or have a narrow therapeutic range.
Article
Our understanding of dysfunction of the gastrointestinal system in patients with Parkinson's disease has increased substantially in the past decade. The entire gastrointestinal tract is affected in these patients, causing complications that range from oral issues, including drooling and swallowing problems, to delays in gastric emptying and constipation. Additionally, small intestinal bacterial overgrowth and Helicobacter pylori infection affect motor fluctuations by interfering with the absorption of antiparkinsonian drugs. The multifaceted role of the gastrointestinal system in Parkinson's disease necessitates a specific and detailed assessment and treatment plan. The presence of pervasive α-synuclein deposition in the gastrointestinal tract strongly implicates this system in the pathogenesis of Parkinson's disease. Future studies elucidating the role of the gastrointestinal tract in the pathological progression of Parkinson's disease might hold potential for early disease detection and development of neuroprotective approaches. Copyright © 2015 Elsevier Ltd. All rights reserved.
Article
One of the major factors affecting oral drug bioavailability is the activity of intestinal transport proteins, particularly for the drugs that undergo absorption by active transport mechanism. Many of the active pharmacological agents and the excipients used in their formulation are reported to modulate the activity of these transporters thereby either enhancing or decreasing the drug absorption and its systemic availability. These excipients are considered pharmacologically "inert" and have been used since years in pharmaceutical formulations. Appreciable interest is developing on the data demonstrating the role of excipients in altering the drug absorption across the intestine. Careful selection of the excipients thus is very important. A correctly chosen excipient can enhance the drug bioavailability and thus its therapeutic efficacy without increasing its dose. For locally acting drugs having systemic side effects, a proper excipient could lead to a decrease in its systemic absorption, thus reducing its side effects. This review focuses on the current findings of the excipients identified to modulate the activity of transporters, their mechanism of modulating the transporter′s activity and various formulation strategies using these excipients to enhance drug absorption.
Article
The abundance and function of transporter proteins at the plasma membrane is likely to be crucial in drug responsiveness. The detection of Human Concentrative Nucleoside Transporters (hCNTs) function is of interest to predict drug sensitivity due to their ability to transport most nucleoside-derived drugs. In the present study two fluorescent nucleoside analogues, Uridine-furan and Etheno-cytidine, were evaluated as tools to study in vivo nucleoside transporter-related functions. These two molecules showed high affinity interactions with hCNT1 and hCNT3 being also hCNT substrates. Both fluorescent microscopy and flux cytometry experiments showed that Uridine-furan uptake was better suited for distinguishing cells that express or not hCNT1 or hCNT3. These data highlight the usefulness of fluorescent nucleoside derivatives as long as they fulfil the requirements of confocal microscopy and flow cytometry for in vivo analysis of hCNT-related function.
Article
The purpose of the present study was to evaluate and compare the absolute protein expression levels of 28 drug-related transporters in Caco-2 cell monolayers cultured for 2, 3, and 4 weeks. Plasma membrane fractions of Caco-2 cells cultured on Transwell inserts for 2, 3 and 4 weeks were prepared and digested with trypsin, and then simultaneous absolute quantification of 28 transporters and Na(+)/K(+)-ATPase was conducted using our established quantitative targeted absolute proteomic technique. Nine transporters and Na(+)/K(+)-ATPase were detected. MDR1, BCRP, PEPT1, OSTα and OSTβ were highly expressed (greater than 1 fmol/μg protein), while MRP2, MRP4, OATP2B1 and MCT1 were moderately expressed (0.328-0.871 fmol/μg protein). No significant difference was observed in the protein expression levels of these transporters or Na(+)/K(+)-ATPase among the 2-, 3- and 4-week cultures. The other 19 transporters, including MRP1, MRP3, OATP1A2, OATP3A1, OATP4A1, and OATP1B3, were not detected. This information about the rank order of transporter protein expression will be useful to predict what transporter(s) are likely or unlikely to influence the permeability of various compounds across monolayers of Caco-2 cells, which are widely used in drug development studies. Copyright © 2014 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.
Article
The efflux transporter, P-glycoprotein (P-gp), located in the apical membranes of intestinal absorptive cells, can reduce the bioavailability of a wide range of orally administered drugs. A number of surfactants/excipients have been shown to inhibit P-gp, and thus potentially enhance drug absorption. In this study, the improved everted gut sac technique was used to screen excipients for their ability to enhance the absorption of digoxin and celiprolol in vitro. The most effective excipients with digoxin were (at 0.5%, w/v): Labrasol > Imwitor 742 > Acconon E = Softigen 767 > Cremophor EL > Miglyol > Solutol HS 15 > Sucrose monolaurate > Polysorbate 20 > TPGS > Polysorbate 80. With celiprolol, Cremophor EL and Acconon E had no effect, but transport was enhanced by Softigen 767 > TPGS > Imwitor 742. In vivo, the excipients changed the pharmacokinetic profile of orally administered digoxin or celiprolol, but without increasing the overall AUC. The most consistent change was an early peak of absorption, probably due to the higher concentration of excipient in the proximal intestine where the expression of P-gp is lower. These studies show that many excipients/surfactants can modify the pharmacokinetics of orally administered drugs that are P-gp substrates.
Article
Intestinal transporters are crucial determinants in the oral absorption of drugs. We therefore studied mRNA expression (N=33) and absolute protein content (N=10) of clinically relevant transporters in healthy epithelium of the duodenum, proximal and distal jejunum and ileum and the ascending, transversal, descending and sigmoidal colon of six organ donors (24-54 years). In the small intestine, the abundance of nearly all studied proteins ranged between 0.2-1.6 pmol/mg with the exception of OCT3 (<0.1 pmol/mg) and PEPT1 (2.6-4.9 pmol/mg) which accounted for ~50% of all measured transporters. OATP1A2 was not detected in any intestinal segment. ABCB1, ABCG2, PEPT1 and ASBT were significantly higher abundant in jejunum/ileum than in colon. In contrast to this, ABCC2, ABCC3 and OCT3 expression was found to be highest in colon. Site-dependent expression was confirmed for ABCB1 and ASBT and significant correlations between mRNA and protein levels for ABCG2, ASBT, OCT3 and PEPT1 in the small intestine. Our data provide further physiological pieces in the puzzle required to predict intestinal drug absorption in man.
Article
This review summarizes the current knowledge on anatomy and physiology of the human gastrointestinal tract in comparison with that of common laboratory animals (dog, pig, rat and mouse) with emphasis on in vivo methods for testing and prediction of oral dosage form performance. A wide range of factors and methods are considered in addition, such as imaging methods, perfusion models, models for predicting segmental/regional absorption, in vitro in vivo correlations as well as models to investigate the effects of excipients and the role of food on drug absorption. One goal of the authors was to clearly identify the gaps in todays knowledge in order to stimulate further work on refining the existing in vivo models and demonstrate their usefulness in drug formulation and product performance testing.
Article
Drug absorption from the gastrointestinal (GI) tract is a highly complex process dependent upon numerous factors including the physicochemical properties of the drug, characteristics of the formulation and interplay with the underlying physiological properties of the GI tract. The ability to accurately predict oral drug absorption during drug product development is becoming more relevant given the current challenges facing the pharmaceutical industry. Physiologically-based pharmacokinetic (PBPK) modeling provides an approach that enables the plasma concentration-time profiles to be predicted from preclinical in vitro and in vivo data and can thus provide a valuable resource to support decisions at various stages of the drug development process. Whilst there have been quite a few successes with PBPK models identifying key issues in the development of new drugs in vivo, there are still many aspects that need to be addressed in order to maximize the utility of the PBPK models to predict drug absorption, including improving our understanding of conditions in the lower small intestine and colon, taking the influence of disease on GI physiology into account and further exploring the reasons behind population variability. Importantly, there is also a need to create more appropriate in vitro models for testing dosage form performance and to streamline data input from these into the PBPK models. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the current status of PBPK models available. The current challenges in PBPK set-ups for oral drug absorption including the composition of GI luminal contents, transit and hydrodynamics, permeability and intestinal wall metabolism are discussed in detail. Further, the challenges regarding the appropriate integration of results from in vitro models, such as consideration of appropriate integration/estimation of solubility and the complexity of the in vitro release and precipitation data, are also highlighted as important steps to advancing the application of PBPK models in drug development. It is expected that the "innovative" integration of in vitro data from more appropriate in vitro models and the enhancement of the GI physiology component of PBPK models, arising from the OrBiTo project, will lead to a significant enhancement in the ability of PBPK models to successfully predict oral drug absorption and advance their role in preclinical and clinical development, as well as for regulatory applications.
Article
Sarpogrelate is a selective 5-hydroxytryptamine receptor subtype 2A antagonist that inhibits platelet aggregation and vasoconstriction. The aim of this study was to compare the pharmacokinetics of a sarpogrelate controlled-release formulation (CR) with those of the immediate-release formulation (IR). The effect of food on the pharmacokinetics of CR sarpogrelate was also evaluated. A randomized, open-label, 3-period, 3-treatment crossover study was conducted in 50 healthy male subjects. Subjects were allocated into one of six sequence groups. In one period, a 100-mg IR formulation was administered three times at 6-h intervals, and in the other two periods, a 300-mg CR formulation was administered once to fasting and once to fed subjects. Each period was separated by a 7-day washout period. Serial blood samples were collected up to 24 h after the first drug administration in each period. The plasma concentrations of sarpogrelate were analysed by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated by non-compartmental methods. After the administration of the IR formulation, the plasma concentration reached a peak at 0·48 h and the drug was eliminated with a half-life (t1/2 ) of 0·7 h. After administration of the CR formulation, the plasma concentration reached a peak at 0·5 h and the drug was eliminated with a t1/2 of 3·23 h. The geometric mean ratios (CR/IR) for sarpogrelate area under the plasma concentration-time curve (AUC) and the maximum plasma drug concentration (Cmax) were 1·2040 (90% confidence interval (CI): 1·0992-1·3188) and 0·9462 (90% CI: 0·8504-1·0529). When CR was administered to fed subjects, the time to peak concentration was prolonged to 3·97 h and t1/2 was shortened to 1·45 h. The geometric mean ratios (fasting/fed) for sarpogrelate AUC and Cmax were 0·8573 (90% CI: 0·7687-0·9561) and 0·6452 (90% CI: 0·5671-0·7341). After the administration of CR and IR formulations of the same daily dose of sarpogrelate hydrochloride, the overall systemic exposure was slightly higher for the CR than for the IR formulation, whereas peak concentration was comparable between the two formulations. Food reduced the bioavailability of sarpogrelate CR.
Article
Published evidence on established and theorized effects of celiac disease on drug absorption and pharmacokinetics is reviewed. Patients with celiac disease develop a variety of gastric disorders requiring oral medications, but the impact of damage to intestinal villi and other celiac disease sequelae on drug absorption remains poorly understood. A review of the pertinent literature (English-language articles on research in adults published during the period 1970-August 2012) identified several reports of altered drug absorption mechanisms in patients with celiac disease, including accelerated or delayed gastric emptying, increased permeability of jejunal mucosa, changes in intraluminal pH, decreased intestinal surface area, and reduced intestinal cytochrome P-450 enzymes. A small number of published studies suggest that celiac disease may be associated with altered drug absorption, resulting in higher serum concentrations of propranolol, lower peak concentrations of acetaminophen and practolol, higher dosing requirements with levothyroxine, impaired or delayed absorption of certain antibiotics, and other pharmacokinetic effects with a potential impact on medication efficacy and toxicity. However, these studies involved very small patient samples and were poorly controlled, with some yielding contradictory results. More and larger pharmacokinetic studies in patients with celiac disease-especially studies of drugs that are dosed empirically or are not amenable to dosage adjustment according to vital signs or laboratory values-are needed. Given the sometimes conflicting data on drug absorption in the context of celiac disease, cautious medication selection, dosage adjustment, and monitoring for efficacy and potential adverse effects are advised.
Article
In this review, the gross physiology of the gastrointestinal tract of dogs is compared with that of humans, particularly as it pertains to drug absorption and dosage-form performance. Gastrointestinal (GI) motility and pH are the main parameters considered. Although similar motility patterns and pH profiles prevail in the two species for the most part, there are some differences that could affect the time profile and extent of drug absorption. These include slower gastric emptying in the fed state, faster small intestine transit, and higher and more variable intestinal pH in dogs compared with humans. An attempt is made to identify drug and dosage-form properties that would lead to differences in drug absorption in the two species, e.g., drug physicochemical properties, dosage-form size, and pH dependency of dosage-form release characteristics.
Article
The focus of this review is on the pharmaceutical relevance of the intestinal peptide transporter PepT1. The review is limited to the progress made in the field over the past two years. Much of this progress is being driven by the prevailing view that PepT1 can be used for drug delivery purposes. Studies have indeed shown that several drugs, prodrugs and drug candidates gain entry into the systemic circulation via PepT1. Very recent examples are prodrugs of zanamivir, oseltamivir and didanosine.
Article
Resveratrol exhibits a variety of biological and pharmacological activities despite its extensive metabolism to sulfates and glucuronides in the intestine and liver. The metabolism of resveratrol is cell specific and strongly correlates with enzyme expression levels. However, a high rate of biotransformation, in concert with the action of the efflux transporters MRP2, MRP3, and ABCG2, reduces intracellular resveratrol concentrations, and may thereby decrease its pharmacological activity. Interestingly, biotransformation is also dependent on disease status. For example, significantly greater sulfation of resveratrol occurs in human breast tumor tissue than in adjacent nonmalignant tissue. The observed differences, however, do not correlate with the expression of sulfotransferases responsible for catalyzing resveratrol sulfation, but rather with significantly higher steroid sulfatase mRNA levels. The in vitro activity of resveratrol sulfates may not necessarily reflect their in vivo function, given the fact that ubiquitously existing human sulfatases can convert the metabolites back to active resveratrol in humans.
Article
The rate-limiting step to absorption of drugs from the gastrointestinal (GI) tract is often dissolution from the dosage form. Consideration of the Noyes-Whitney dissolution model shows that drug diffusivity, solubility in the gastrointestinal contents, the surface area of the solid wetted by the lumenal fluids and the GI hydrodynamics all play a role in determining the in vivo dissolution rate. Solubility in the GI contents is determined by aqueous solubility, crystalline form, drug lipophilicity, solubilization by native surfactants and co-ingested foodstuffs, and pKa in relation to the GI pH profile. Compounds with aqueous solubilities lower than 100 μg/ml often present dissolution limitations to absorption. The dose:solubility ratio of the drug provides an estimate of the volume of fluids required to dissolve an individual dose, and when this volume exceeds 1 l, dissolution is often problematic. The surface area of a drug available for dissolution depends on the particle size of the solid and its ability to be wetted by lumenal fluids. Other physiological factors that can play a role in dissolution include the viscosity of the lumenal contents, through its effect on the diffusivity, and mixing and flow patterns within the gut. In order to better predict in vivo dissolution of drugs, dissolution tests which more adequately simulate the physiological conditions are needed.