Biopharmaceutics & Drug Disposition (Biopharm Drug Dispos )

Publisher: John Wiley and Sons

Description

The Journal publishes original reports of studies in biopharmaceutics drug disposition and pharmacokinetics especially those which have a direct relation to the therapeutic use of drugs. This includes human pharmacological studies and therapeutic response and toxicity related to plasma and tissue concentrations of drugs and their metabolites. Research on factors affecting the disposition of the clinical response to drugs and on the design of drug dosage regimens and the treatment of overdose based on pharmacokinetic principles are accepted. Papers on analytical methodology in vitro drug metabolism and on animal models are also published provided that either they facilitate the preceding types of investigation or they are related to the use of drugs in man. The Journal also publishes review articles.

Impact factor 2.18

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    Impact factor
  • 5-year impact
    1.73
  • Cited half-life
    8.10
  • Immediacy index
    0.57
  • Eigenfactor
    0.00
  • Article influence
    0.46
  • Website
    Biopharmaceutics & Drug Disposition website
  • Other titles
    Biopharmaceutics & drug disposition (Online), Biopharmaceutics & drug disposition, Biopharmaceutics and drug disposition
  • ISSN
    1099-081X
  • OCLC
    43974207
  • Material type
    Document, Periodical, Internet resource
  • Document type
    Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

John Wiley and Sons

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    • See Wiley-Blackwell entry for articles after February 2007
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    • 'John Wiley and Sons' is an imprint of 'Wiley'
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Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: The effect of concomitant drugs having a cytochrome P450 (CYP) 3A inhibitory potency on tacrolimus exposure was predicted from in vitro metabolism results. In this study, the IC50 values of concomitant drugs on the formation of M-I, the major metabolite of tacrolimus, were determined, and the effect on oral exposure (AUCp.o. ) of tacrolimus was assessed from static models. When absorbed fraction (Fa ) of 0.97, intestinal wall availability (Fg ) of 0.27, and fraction metabolized by CYP3A (fm(CYP3A) ) of 0.8 were used, the least bias was observed for the prediction of the AUCp.o. of tacrolimus. The relationship of IC50 values of 11 inhibitors between tacrolimus and typical CYP3A substrates (midazolam and testosterone) was also analyzed. We found a strong correlation between IC50 values of tacrolimus and typical CYP3A substrates (r(2) ≥ 0.85). The predictability of the effect of inhibitors on tacrolimus AUCp.o. was investigated based on the same static models with the use of published IC50 values for midazolam and testosterone. The bias for the prediction of tacrolimus AUCp.o. was minimal with the use of IC50 values determined using tacrolimus itself as a substrate. These results suggest that tacrolimus itself is still the best choice for predicting AUCp.o. of tacrolimus, although our findings suggest that midazolam or testosterone may be used instead of tacrolimus to roughly estimate (predicted AUCp.o. within approximately 2-fold range of observed values) the effect of CYP3A inhibitors on tacrolimus AUCp.o. . This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 01/2015;
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    ABSTRACT: PurposeGastric emptying (GE) is often reported to be slower and more irregular in premature neonates than in older children and adults. The aim of this study was to investigate the impact of age and other covariates on the rate of GE.Methods The effect of age on the mean gastric residence times (MGRT) of liquid and solid food was assessed by analysing 49 published studies of 1457 individuals, aged from 28 weeks gestation to adults. The data were modelled using the nonlinear mixed-effects approach within NONMEM version 7.2 (ICON, Dublin, Ireland), with evaluation of postnatal age, gestational age, and meal type as covariates. A double Weibull function was selected as a suitable model since it could account for the typical biphasic nature of GE.ResultsAge was not a significant covariate for GE but meal type was. Aqueous solutions were associated with the fastest emptying time (mean simulated gastric residence time of 45 minutes) and solid food was associated with the slowest (98 minutes).Conclusions These findings challenge the assertion that GE is different in neonates, as compared with older children and adults due to age, and they reinforce the significance of food type in modulating GE. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 01/2015;
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    ABSTRACT: Previous work has indicated that there is increased protein expression of multidrug resistance-associated protein 3 (MRP3) in the liver samples when patients were treated with omeprazole compared with those who were not. However, the evidence is still lacking to show the mechanisms underlying that induction. This study aimed to assess changes in fold-induction of MRP3 mRNA and protein expression over controls in omeprazole-treated HepG2 cells after transient transfection of human MRP3 siRNA, or after pretreatment of actinomycin D (Act-D). Furthermore, MRP3 siRNA knock-down or MRP-specific inhibition (indomethacin) was used to determine whether induced MRP3 protein by omeprazole could possess enhanced efflux transport. The results demonstrated that omeprazole induced MRP3 mRNA and protein expression in a concentration- and time-dependent manner. Moreover, that induction was almost completely abolished by addition of human MRP3 siRNA and also by pretreatment of Act-D, respectively. In addition, the decay rate of MRP3 mRNA in vehicle- and omeprazole-treated cells was similar in the presence of Act-D, suggesting transcriptional up-regulation of MRP3 mRNA expression by omeprazole. Most importantly, omeprazole induced MRP3 efflux transport activity as measured by 5-carboxyfluorescein assay in the presence or absence of human MRP3 siRNA or indomethacin. We conclude that omeprazole can induce MRP3 mRNA and protein expression and enhance MRP3 efflux transport activity through the transcriptional up-regulation, and that omeprazole can also induce other MRP transporters. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 01/2015;
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    ABSTRACT: PurposeTo investigate the PK/PD interaction between IRB and HCT in normotensive subjects.MethodsA three-way crossover study. Serial drug concentrations and drug effects, including SBP, DBP and HR were monitored after administration of IRB and HCT alone and in combination. The data were fitted to PK/PD model and the parameters for IRB and HCT when administered alone and in combination were compared.ResultsThe plasma profiles for IRB and HCT followed the two-compartment model after a single dose. IRB PK parameters were not affected by HCT; however IRB decreased HCT AUC by 25% and increased its clearance by 25%. There were no significant changes in HR after each drug alone or the combination. IRB plus HCT had greater BP lowering effect compared to IRB alone, despite the unchanged IRB PK. The relationship between IRB plasma concentration and its effects plotted in chronological order showed anticlockwise hysteresis. The PD parameter estimates for the effect of IRB on SBP, when administered with HCT were significantly different from those when IRB was administered alone. This was manifested by 25% increase in Emax, and 40% decrease in EC50, suggesting synergistic BP lowering effect for the combination. While parameter estimates for the effect of IRB on DBP were changed by HCT, however the differences were only significant for EC50.ConclusionA limited potential for clinically significant interactions between IRB and HCT at the given doses were observed; therefore, no dosage adjustments were recommended for either drug when used together. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 12/2014;
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    ABSTRACT: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to relieve pain and decrease inflammation. Several clinical studies have reported that NSAIDs inhibit uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes. Therefore, we evaluated the inhibitory potential of 15 NSAIDs on the activities of six UGT isoforms (i.e., UGT1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) in human liver microsomes (HLMs). Among the 15 NSAIDs tested here, mefenamic acid and diclofenac inhibited all UGTs tested in this study. Piroxicam and niflumic acid inhibited UGT1A9 activity (IC50 = 73.8 μM and 0.38 μM, respectively) and naproxen selectively inhibited UGT2B7 activity (IC50 = 53.1 μM), whereas it did not inhibit the other UGTs tested (IC50 > 200 μM). Diflunisal inhibited the UGT1A1 (IC50 = 33.0 μM) and UGT1A9 (IC50 = 19.4 μM). Acetaminophen, fenoprofen, ibuprofen, ketoprofen, meloxicam, phenylbutazone, salicylic acid, and sulindac showed negligible inhibitory effects on the six UGTs (IC50 > 100 μM). These results suggest that some NSAIDs have the potential to inhibit UGTs in vitro. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 12/2014;
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    ABSTRACT: Here, we summarize the discussion topics at the 2013 AAPS symposium on “Dealing with complex drug-drug interactions: towards mechanistic models”. The unmanageable adverse events caused by drug-drug interactions (DDIs), leading to market withdrawal or restriction in use, are increasingly being avoided with our improvement in quantitative prediction of DDIs early in drug development, and that significant challenges remain when inhibitor drugs and/or metabolites affect not one but multiple pathways of clearance. Physiologically based pharmacokinetic (PBPK) models, in combination with established in vitro-to-in vivo extrapolations of intestinal and hepatic disposition, have been successfully applied to predict clinical pharmacokinetics and DDIs, especially for drugs with CYP-mediated metabolism, and to explain transporter-mediated and complex DDIs. Although continuous developments are being made towards improved mechanistic prediction of the transporter-enzyme interplay in the hepatic and intestinal disposition and characterizing the metabolites contribution to DDIs, prediction of both enzyme and transporter mediated DDI remains difficult. Regulatory guidelines recommended use of PBPK modeling for the quantitative prediction and evaluation of DDIs involving multiple perpetrators and metabolites. Such mechanistic modeling approaches culminate to the consensus that modeling is helpful in predicting DDIs and quantitatively rationalize clinical findings in complex situations. Furthermore, they provide the basis for the prediction and/or understanding pharmacokinetics in different populations: renally impaired, pediatrics, or ethnic groups where the conduct of clinical studies might not be feasible in early drug development stages, but some guidance on management of dosage is necessary. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 12/2014;
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    ABSTRACT: Subcutaneous administration of biologics is highly desirable; however, incomplete bioavailability after sc administration remains a major challenge. In this work we investigated the effects of excipient dependent hyper-osmolarity on lymphatic uptake and plasma exposure of rituximab as a model protein. Using Swiss Webster (SW) mice as our animal model, we compared the effects of NaCl, mannitol and, O-Phospho-L-Serine (OPLS) on plasma concentration of rituximab over 5 days after sc administration. We observed an increase in plasma concentrations in animals administered rituximab in hypertonic buffer solutions, as compared to isotonic buffer. Bioavailability, as estimated by our pharmacokinetic model, increased from 29% in isotonic buffer to 54% in hypertonic buffer containing NaCl, to almost complete bioavailability in hypertonic buffers containing high dose OPLS or mannitol. This improvement in plasma exposure is due to improved lymphatic trafficking as evident from the increase in the fraction of dose trafficked through the lymph node in the presence of hypertonic buffers. The fraction of the dose trafficked through the lymphatic, as estimated by the model, increased from 0.05 % in isotonic buffer to 13% in hyper-tonic buffer containing NaCl to about 30% for hypertonic buffers containing high dose OPLS and mannitol. Our data suggests that hypertonic solutions may be a viable option to improve sc bioavailability. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 11/2014;
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    ABSTRACT: GSK5182 (4-[(Z)-1-[4-(2-Dimethylaminoethyloxy)phenyl]-hydroxy-2-phenylpent-1-enyl]phenol) is a specific inverse agonist for estrogen-related receptor γ, a member of the orphan nuclear receptor family that has important functions in development and homeostasis. This study was performed to elucidate the metabolites of GSK5182 and to characterize the enzymes involved in its metabolism. Incubation of human liver microsomes with GSK5182 in the presence of NADPH resulted in the formation of three metabolites, M1, M2, and M3. M1 and M3 were identified as N-desmethyl-GSK5182 and GSK5182 N-oxide, respectively, on the basis of liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis. M2 was suggested to be hydroxy-GSK5182 through interpretation of its MS/MS fragmentation pattern. In addition, the specific cytochrome P450 (P450) and flavin-containing monooxygenase (FMO) isoforms responsible for GSK5182 oxidation to the three metabolites were identified using a combination of correlation analysis, chemical inhibition in human liver microsomes, and metabolism by expressed recombinant P450 and FMO isoforms. GSK5182 N-demethylation and hydroxylation is mainly mediated by CYP3A4, whereas FMO1 and FMO3 contribute to the formation of GSK5182 N-oxide from GSK5182. The present data will be useful to understand the pharmacokinetics and drug interactions of GSK5182 in vivo. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 11/2014;
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    ABSTRACT: Background Etomidate is a rapid-onset, short-acting hypnotic medication administered for induction of anesthesia. It is currently approved by the Food and Drug Administration for use in older children and adults. Pharmacokinetic data to help guide dosing in neonates and infants is lacking.Objective The aim of this study was to determine the pharmacokinetics of etomidate in neonates and infants with congenital heart disease undergoing cardiac surgery.Methods Four neonates and sixteen infants, postnatal age 0.3 – 11.7 months, requiring open-heart surgery received 0.3 mg/kg of etomidate administered as a single intravenous dose prior to surgery. Blood sampling for plasma etomidate concentration occurred immediately following etomidate administration until the initiation of cardiopulmonary bypass. A population pharmacokinetic approach using nonlinear mixed–effects modeling was applied to characterize etomidate pharmacokinetics.ResultsThe pharmacokinetics of etomidate was described by a two-compartment model with first-order elimination. An allometric weight-based model was applied to scale results to a 70 kg adult. Covariates including age and cardiac physiology were not found to significantly impact etomidate pharmacokinetics. The study population was found to have a central and intercompartmental clearance of 0.624 L/min/70-kg and 0.44 L/min/70-kg, respectively; central and peripheral distribution volume of 9.47 and 22.8 L/70-kg, respectively. Inter-individual variability was between 94-142% for all parameters and residual variability was 29%.Conclusions The clearance of etomidate is lower in neonates and infants with congenital heart disease compared to published values for older children without congenital heart disease. In addition, etomidate pharmacokinetics is highly variable in this pediatric cardiac population. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 11/2014;
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    ABSTRACT: The bioavailability of orally administered therapies are often significantly limited in the human intestine by the metabolic activities of Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). Predicting whether candidate compounds induce CYP3A4 and P-gp is a crucial stage in the drug development process, as drug-drug interactions may result in the induction of intestinal CYP3A4 and P-gp. However, the assay systems needed to evaluate both CYP3A4 and P-gp induction in the intestine are yet to be established. To address this urgent requirement, we used LS174T cells to create two stable cell lines expressing the CYP3A4 or ATP-binding cassette subfamily B member 1 (ABCB1, encoding P-gp) reporter genes. First, we tested these stable cells by treatment with 1α, 25-dihydroxyvitamin D3 (1,25(OH)2D3), all-trans-retinoic acid (ATRA), and 9-cis-retinoic acid (9-cis RA) that induce CYP3A4 and P-gp in the intestines. All these compounds significantly increased both CYP3A4 and ABCB1 reporter activities in the stable cell lines. To simultaneously assess induction of CYP3A4 and ABCB1, both stable cells were co-cultivated to measure their reporter activities. The mixed cells showed a significant increase in the CYP3A4 and ABCB1 reporter activities following treatment with 1,25(OH) 2D3, ATRA, and 9-cis RA. These activity levels were maintained after passaging for more than 20 times and following multiple freeze-thaw cycles. These results demonstrate that our established cell lines can be used to simultaneously evaluate CYP3A4 and ABCB1 induction in the intestines, providing a valuable in vitro model for the evaluation of future drug candidates. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 11/2014;
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    ABSTRACT: The purpose of this study was to characterize the brain-to-blood efflux transport of amantadine across the blood-brain barrier (BBB). The apparent in vivo efflux rate constant for [3H]amantadine from the rat brain (keff) was found to be 1.53 × 10−2 min−1 after intracerebral microinjection using the Brain Efflux Index method. The efflux of [3H]amantadine was inhibited by 1-methyl-4-phenylpyridinium (MPP+), a cationic neurotoxin, suggesting that amantadine transport from the brain to the blood across the BBB is potentially involved in the rat plasma membrane monoamine transporter (rPMAT). On the other hand, other selected substrates for organic cation transporters (OCTs) and organic anion transporters (OATs), as well as inhibitors of P-glycoprotein (P-gp), did not affect the efflux transport of [3H]amantadine. In addition, in vitro studies using an immortalized rat brain endothelial cell line (GPNT) showed that the uptake and retention of [3H]amantadine by the cells was not changed by the addition of cyclosporin, which is an inhibitor of P-gp. However, cyclosporin affected the uptake and retention of rhodamine123. Finally, the initial brain uptake of [3H]amantadine was determined using an in situ mouse brain perfusion technique. Notably, the brain uptake clearance for [3H]amantadine was significantly decreased with the co-perfusion of quinidine or verapamil, which are cationic P-gp inhibitors, while MPP+ did not have a significant effect. We thus conclude that while P-gp is not involved, it is possible that rPMAT and the cationic drug-sensitive transport system participate in the brain-to-blood efflux and the blood-to-brain influx of amantadine across the BBB, respectively. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 11/2014;
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    ABSTRACT: Menthol is widely used as a constituent of functional foods and chemical drugs. In the present study, we investigated changes in the pharmacokinetic behavior of intravenously administered midazolam (MDZ), a probe for CYP3A, when rats were treated with menthol. We also examined which isoforms of CYP3A1 and 3A2 were menthol-inducible and contributed to the altered disposition of MDZ. Menthol was intraperitoneally administered to rats once daily for 3 days at a dose of 10 mg/kg, while control rats received vehicle alone. The pharmacokinetic examination of intravenously administered MDZ revealed that serum MDZ concentrations at each sampling point were lower in menthol-treated rats than in control rats. Regarding the pharmacokinetic parameters of the menthol-treated group, the area under the curve (AUC) was significantly decreased and, correspondingly, the elimination rate constant at terminal phase (ke) was significantly increased without significant changes in the volume of distribution at steady state (Vdss). The metabolic production of the 1’-hydroxylated and 4’-hydroxylated forms of MDZ by hepatic microsomes was significantly greater in menthol-treated rats than in control rats. The expression levels of mRNA and protein for hepatic CYP3A2 were more than 2.5-fold higher than the control levels when rats were treated with menthol, whereas no changes were observed in the expression levels of CYP3A1. These results indicate that menthol enhanced the elimination clearance of MDZ by inducing hepatic CYP3A2 and that careful attention should be paid when menthol is ingested in combination with drugs that act as substrates for CYP3A. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 11/2014;
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    ABSTRACT: Teneligliptin is a Type 2 diabetes drug that has an inhibitory effect on dipeptidyl peptidase-4. The aim of this study was to establish a physiologically based pharmacokinetic (PBPK) model to elucidate in detail the pharmacokinetics of teneligliptin. A PBPK model of teneligliptin was developed using the population-based Simcyp simulator incorporating the results of in vitro and in vivo studies. Model validation was conducted by comparison of simulated teneligliptin plasma concentrations with those from clinical trials. Using the PBPK model, we examined predicted drug–drug interactions with concomitant medication. The robustness of the PBPK model was demonstrated by the accurate simulation of clinically measured plasma concentrations of teneligliptin after oral administration in different ethnic groups, in subjects belonging to different age groups, and in patients with kidney or liver impairment; none of these factors were incorporated during model development. The fraction absorbed and intestinal availability of teneligliptin predicted by the model were 0.62 and 0.99, respectively. The predicted ratios of areas under the time–concentration curves (AUCs) in patients with moderate and severe renal impairment who were concomitantly administered ketoconazole, a potent inhibitor of P450 3A4, were, respectively, 2.1- and 2.2-fold those in healthy adults who were given teneligliptin alone. We constructed a robust PBPK model reflecting the pharmacokinetic properties of teneligliptin. The final optimized PBPK model enabled us to elucidate in detail the factors affecting the pharmacokinetics of teneligliptin and to predict changes in exposure in drug–drug interactions or in specific populations. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 11/2014;
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    ABSTRACT: The potent and selective phosphodiesterase 4 inhibitor ASP3258 is a novel therapeutic agent for asthma and chronic obstructive pulmonary disease (COPD). After a single oral administration to rats, ASP3258 is rapidly absorbed with a bioavailability of 106%. In situ absorption data indicated that ASP3258 is mainly absorbed in the small intestine. Tissue distribution data after oral administration of 14C-ASP3258 showed rapid and extensive distribution to various tissues. Excluding the gastrointestinal tract, the tissues with the highest concentrations were liver, heart, and plasma. Liquid chromatography-nuclear magnetic resonance spectroscopy data revealed that O-glucuronidation of the carboxylic acid moiety of ASP3258 (formation of an acyl glucuronide) plays a key role in metabolism. We found no indication that the acyl glucuronide reacted with proteins in plasma or tissues. When 14C-ASP3258 was orally administered to intact rats, urinary and fecal excretion accounted for 1.3% and 100.6% of administered radioactivity, respectively. After a single oral administration of 14C-ASP3258 to bile-cannulated rats, urinary and biliary excretion accounted for 0.7% and 93.8% of administered radioactivity, respectively. These findings suggest that fecal excretion via bile plays an important role in the elimination of ASP3258-derived radioactivity. In vitro metabolic profiles were relatively similar among species examined, suggesting that our findings in rats may help us to understand pharmacokinetics, efficacy, and safety profiles in humans and other species. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 10/2014;
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    ABSTRACT: Recently, the European Medicines Agency (EMA) published the new draft guideline on the pharmacokinetic and clinical evaluation of modified release (MR) formulations. The draft guideline contains the new requirement of performing multiple dose (MD) bioequivalence studies, in case that the MR formulation is expected to show ‘relevant’ drug accumulation at steady state (SS). This new requirement reveals three fundamental issues, which are discussed in the current work: Firstly, the measurement for the extent of drug accumulation (MEDA) predicted from single dose (SD) study data; secondly, its relationship with the percentaged residual area under the plasma concentration-time curve (AUC) outside the dosing interval (τ) after SD administration, %AUC(τ-∞)SD; and thirdly, the rationale for a threshold of %AUC(τ-∞)SD that predicts ‘relevant’ drug accumulation at SS.This work revealed that the accumulation ratio RA,AUC, derived from the ratio of the time-averaged plasma concentrations during τ at SS and after SD administration, respectively, is the ‘preferred’ MEDA for MR formulations. A causal relationship was derived between %AUC(τ-∞)SD and RA,AUC, which is valid for any drug (product) that shows (dose- and time-)linear pharmacokinetics regardless of the shape of the plasma concentration-time curve.Considering AUC thresholds from other guidelines together with the causal relationship between %AUC(τ-∞)SD and RA,AUC indicate that values of %AUC(τ-∞)SD ≤ 20%, resulting in RA,AUC ≤ 1.25, can be considered as leading to non-relevant drug accumulation. Hence, the authors suggest 20% for %AUC(τ-∞)SD as a reasonable threshold and selection criterion between SD or MD study designs for bioequivalence studies of new MR formulations. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 10/2014;
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    ABSTRACT: Erigeron breviscapus (Vant.) Hand-Mazz, a traditional Chinese medicine, is often co-prescribed with clopidogrel for the treatment of ischemic vascular diseases. Scutellarin is the representative bioactive flavonoid isolated from this herb. The aim of this study was to explore the effect of scutellarin on the metabolism and pharmacokinetics of clopidogrel. The in vitro studies using rat liver microsomes showed that scutellarin significantly inhibited the metabolism of clopidogrel. The IC50 value was 2.1 μM. Ten male rats were employed to investigate the effect of scutellarin on the pharmacokinetics of clopidogrel in vivo. After pretreatment with scutellarin, there were significant increase in the AUC0–∞ (from 0.9 ± 0.4 to 1.7 ± 0.6 ng/mL h; P < 0.05) and Cmax (from 0.4 ± 0.1 to 0.9 ± 0.1 ng/mL; P < 0.05) of clopidogrel. The pharmacokinetic data for clopidogrel active metabolite showed significant decrease in AUC0–∞ (18.2 ± 5.6 to 11.4 ± 3.7 ng/mL h; P < 0.05) and Cmax (from 8.2 ± 1.2 to 4.3 ± 0.3 ng/mL; P < 0.05) after pretreatment with scutellarin. Collectively, the metabolism and pharmacokinetics of clopidogrel were significantly affected by scutellarin. This study indicated that potential herb-drug interaction between scutellarin and clopidogrel should be taken into consideration in clinical use. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 09/2014;
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    ABSTRACT: Aliskiren is a substrate for P-glycoprotein (P-gp) and is metabolized via cytochrome P450 3A4 (CYP3A4). The aim of the present study was to assess whether P-gp influenced pharmacokinetics of aliskiren and also if drug–drug interactions (DDIs) mediated through P-gp could be reproduced in cynomolgus monkeys. We investigated the pharmacokinetics of aliskiren in mdr1a/1b gene-deficient (P-gp KO) and wild-type (WT) mice. The area under the plasma concentration-time curve (AUC) following the oral administration of aliskiren was 6.9-fold higher in P-gp KO mice than in WT mice, while no significant differences were observed in the AUC or total plasma clearance following the intravenous administration of aliskiren to P-gp KO mice. We then evaluated the pharmacokinetics of aliskiren and examined DDIs between aliskiren and P-gp inhibitors, such as cyclosporin A (CsA) and zosuquidar, in cynomolgus monkeys. The AUC for aliskiren were 8.3- and 42.1-fold higher after the oral administration of aliskiren with the concomitant oral administration of zosuquidar and CsA at doses of 10 and 30 mg/kg, respectively. In contrast, the AUC after the intravenous and oral administration of aliskiren was not significantly affected by the oral administration of zosuquidar or intravenous administration of CsA, respectively. These results indicated that P-gp strictly limited the intestinal absorption of aliskiren in mice and monkeys, and also that the effects of intestinal P-gp inhibition by CsA or zosuquidar on the pharmacokinetics of aliskiren were sensitively reproduced in monkeys. In conclusion, aliskiren can be used as a sensitive substrate to evaluate intestinal P-gp inhibition in monkeys. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 09/2014;
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    ABSTRACT: The aim of the present study was to investigate the membrane transport mechanisms of choline using human intestinal epithelial LS180 cells. The mRNA of choline transporter-like proteins (CTLs) was expressed significantly in LS180 cells, and the rank order was CTL1 > CTL4 > CTL3 > CTL2 > CTL5. In contrast, the mRNA expression of other choline transporters, organic cation transporter (OCT) 1, OCT2, and high-affinity choline transporter 1 (CHT1), was considerably low in LS180 cells. Five mM unlabeled choline, hemicolinium-3, and guanidine, but not tetraethylammonium, inhibited the cellular uptake of 100 μM choline in LS180 cells. The uptake of choline into LS180 cells was virtually Na+-independent. The uptake of choline was significantly decreased by acidification of extracellular pH; however, it was not increased by alkalization of extracellular pH. In addition, both acidification and alkalization of intracellular pH decreased the uptake of choline, indicating that the choline uptake in LS180 cells is not stimulated by the outward H+ gradient. On the other hand, the uptake of choline was decreased by membrane depolarization along with increasing extracellular K+ concentration. In addition, the Na+-independent uptake of choline was saturable, and the Km value was estimated to be 108 μM. These findings suggest that the uptake of choline into LS180 cells is membrane potential- but not outward H+ gradient-dependent. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 09/2014;
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    ABSTRACT: Macelignan is a natural phenolic compound that possesses many types of health benefits such as anti-inflammation. Here we aim to characterize the metabolism of macelignan via the glucuronidation pathway and to identify the main UGT enzymes involved in macelignan glucuronidation. The rates of glucuronidation were determined by incubating macelignan with UDPGA-supplemented microsomes. Kinetic parameters were derived by fitting an appropriate model to the data. Reaction phenotyping, the relative activity factor (RAF) approach and activity correlation analysis were employed to identify the main UGT enzymes contributing to hepatic metabolism of macelignan. Glucuronidation of macelignan in pooled human liver microsomes (pHLM) was rather efficient with a high CLint (the intrinsic clearance) value of 13.90 ml/min/mg. All UGT enzymes except UGT1A4 and 1A6 showed metabolic activities toward macelignan. UGT1A1 and 2B7 were the enzymes with the highest activities; the CLint values were 4.92 and 2.13 ml/min/mg, respectively. Further, macelignan glucuronidation was significantly correlated with 3-O-glucuronidation of β-estradiol (r = 0.69; p < 0.01) and glucuronidation of zidovudine (r = 0.60; p < 0.05) in a bank of individual HLMs (n = 14). Based on the RAF approach, UGT1A1 and 2B7 respectively contributed 55.40% and 32.20% of macelignan glucuronidation in pHLM. In conclusion, macelignan was efficiently metabolized via the glucuronidation pathway. We also showed that UGT1A1 and 2B7 were probably the main contributors to hepatic glucuronidation of macelignan. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 08/2014;
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    ABSTRACT: Transporter proteins classified into the solute carrier (SLC) transporter superfamily are essential for import of nutrients required for cell survival in organisms. Various SLC transporters are differentially upregulated in cancer cells, and among them, polyspecific organic anion-transporting polypeptides (OATPs) have been proposed to have pathophysiological significance in cancer. This review will briefly introduce OATPs and summarize their proposed roles in cancer, focusing particularly on hormone-dependent breast and prostate cancers. Over the last two decades, compelling evidence has also accumulated that SLC transporters, including OATPs, interact with clinically important anticancer agents and influence their pharmacokinetics, particularly the processes of absorption, elimination and distribution. Therefore, a better understanding of not only the pathophysiological roles, but also the pharmacological effects of OATPs in cancer cells should be helpful in combating human malignant tumors. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 08/2014;