Biopharmaceutics & Drug Disposition (Biopharm Drug Dispos)

Publisher: Wiley

Journal 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.

Current impact factor: 2.18

Impact Factor Rankings

2015 Impact Factor Available summer 2015
2013 / 2014 Impact Factor 2.178
2012 Impact Factor 2.09
2011 Impact Factor 2.074
2010 Impact Factor 1.394
2009 Impact Factor 1.246
2008 Impact Factor 1.542

Impact factor over time

Impact factor

Additional details

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


  • Pre-print
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    • 12 months embargo
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    • On author's personal website, institutional repositories, arXiv, AgEcon, PhilPapers, PubMed Central, RePEc or Social Science Research Network
    • Author's pre-print may not be updated with Publisher's Version/PDF
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    • On a non-profit server
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    • Publisher source must be acknowledged with citation
    • Must link to publisher version with set statement (see policy)
    • If OnlineOpen is available, BBSRC, EPSRC, MRC, NERC and STFC authors, may self-archive after 12 months
    • If OnlineOpen is available, AHRC and ESRC authors, may self-archive after 24 months
    • Publisher last contacted on 07/08/2014
    • This policy is an exception to the default policies of 'Wiley'
  • Classification
    ​ yellow

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: In our study, we investigated the in vitro drug-drug interaction potential of SIPI5357, an arylalkanol-piperazine derivative used in the treatment of depression. Drug-drug interaction occurs via inhibition or induction of enzymes involved in their metabolism. In human liver microsomes, SIPI5357 showed the strongest inhibition of CYP2D6, followed by CYP3A4 (testosterone) and CYP2C8. Inhibition was observed in a concentration-dependent manner, with IC50 values of 18.45 μM, 36.63 μM (CYP3A4/testosterone), 89.23 μM, respectively. SIPI5357 was predicted not to cause significant metabolic drug-drug interaction via inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2E1, or CYP3A4 (midazolam) because the IC50 values for these enzymes were both >100 μM (200 times maximum plasma concentration [Cmax ]). SIPI5357 showed mixed model inhibition of CYP2D6 (Ki =11.12 μM). The value of [I]/Ki for CYP2D6 inhibition by SIPI5357 is below the FDA cutoff value of 0.1; it is therefore reasonable to assume that SIPI5357 will not cause siginificant CYP2D6 inhibition. However, positive controls (50 μM omeprazole and 25 μM rifampin) caused the anticipated CYP induction, but the highest concentration of SIPI5357 (5 μM; 10 times plasma Cmax ) had minimal effect on CYP1A2 and CYP3A4 mRNA levels in freshly isolated human hepatocytes, suggesting that SIPI5357 is not an inducer of these enzymes. However, significant induction of CYP2B6 was observed at 0.5 μM and 5 μM. In conclusion, SIPI5357 might cause drug-drug interaction via induction of CYP2B6. The in vivo drug-drug interaction potential deserves further investigation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 03/2015; DOI:10.1002/bdd.1947
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    ABSTRACT: Malnourishment is a complex condition in which physiopathological changes take place in multiple systems as a result of energy, protein and nutrient deficiency. The purpose of this study was to evaluate, using an experimental animal model, the impact of nutritional status on the pharmacokinetic profile of erlotinib, a reversible, highly selective, human epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor. Two groups of rats - WN (Well-nourished) and UN (Undernourished) - were fed with different diets for 23-26 days. Rats were assigned randomly to one of three erlotinib treatments (N=42) consisting of a single dose administered intravenously (IV), via oral solution or via oral suspension. Blood samples were assayed for erlotinib concentration. A population pharmacokinetic model was developed and pharmacokinetic parameters obtained in UN rats were compared with those in WN rats. Erlotinib clearance suffered a 5% decrease in mild-undernutrition status. Moreover, when the drug was administered orally as a suspension, the extent and rate of absorption underwent a 20% increase in UN rats. The results of this study might help to explain, at least in part, the variability of erlotinib treatment and could represent the first step towards establishing new dosage guidelines for the treatment of undernourished cancer patients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 03/2015; DOI:10.1002/bdd.1948
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    ABSTRACT: With traditional non-compartmental methods, it is challenging to deconstruct plasma concentration versus time curves to assess the influence of individual doses. In this study, we describe the application of a mathematical approach used to deconstruct a single dose curve using data derived from the second, third, fourth, or n(th) dosing interval. Using data from a prospective clinical trial we demonstrate that this approach reliably estimates pharmacokinetic parameters measured following two doses of zolpidem tartrate. Additionally, we demonstrate the application of this approach using previously published data from a single- and multiple-dose pharmacokinetic study of the antibiotic gatifloxacin. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 03/2015; DOI:10.1002/bdd.1949
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    ABSTRACT: Cudratricusxanthone A (CTXA), isolated from the roots of Cudrania tricuspidata, exhibits several biological activities; however, metabolic biotransformation was not investigated. Therefore, we investigated metabolites of CTXA and characterized major metabolic enzymes engaged in human liver microsomes (HLMs) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). CTXA was incubated with HLMs or human recombinant CYPs and UGTs, and analyzed by LC-MS/MS equipped electrospray ionization (ESI) to qualify and quantify its metabolites. In total, 8 metabolites were identified: M1-M4 were identified as mono-hydroxylated metabolites during Phase I, and M5-M8 were identified as O-glucuronidated metabolites during Phase II in HLMs. Moreover, these metabolite structures and a metabolic pathway were identified by elucidation of MS(n) fragments and formation by human recombinant enzymes. M1 was formed by CYP2D6, and M2-M4 were generated by CYP1A2 and CYP3A4. M5-M8 were mainly formed by UGT1A1, respectively. While investigating the biotransformation of CTXA, we identified 8 metabolites of CTXA by CYPs and UGTs; these data will be valuable for understanding in vivo metabolism of CTXA. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 03/2015; DOI:10.1002/bdd.1943
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    ABSTRACT: Little is known about the uptake of drugs into the human heart although, it is of great importance nowadays, when science desires to predict tissue level behavior rather than measure it. Although the drug concentration in cardiac tissue seems better predictor for physiological and electrophysiological changes than its level in plasma, the knowledge of its value is very limited. Tissue to plasma partition coefficients (Kp) come to rescue since they characterize the distribution of a drug among tissue being one of the input parameters in the physiologically based pharmacokinetic (PBPK) models. The article reviews cardiac surgery and forensic medical studies to provide a reference for drug concentrations in human cardiac tissue. Firstly, the focus is put on whether a drug penetrates into heart tissue at a therapeutic level; provided values refer to antibiotics, antifungals and anticancer drugs. Drugs that directly affect cardiomyocytes' electrophysiology are another group of interest. Measured levels of amiodarone, digoxin, perhexiline and verapamil in different sites in human cardiac tissue where the compounds might meet ion channels, gives an insight into how these more lipophilic drugs penetrate into the heart. Much data are derived from postmortem studies and they provide insight in the cardiac distribution of more than 200 drugs. The analysis depicts potential problems in defining the active concentration location, what may indirectly suggest multiple mechanisms involved in the drug distribution within the heart. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 03/2015; DOI:10.1002/bdd.1944
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    ABSTRACT: Loxoprofen (LX) is a prodrug-type non-steroidal anti-inflammatory drug which is used as not only an oral drug but also as a transdermal formulation. As a pharmacologically active metabolite, the trans-alcohol form of LX (trans-OH form) is generated after oral administration to humans. The objectives of this study are to evaluate the generation of the trans-OH form in human in vitro skin and to identify the predominant enzyme for its generation. In the permeation and metabolism study using human in vitro skin, both permeation of LX and formation of the trans-OH form increased in a time- and dose-dependent manner after the application of LX gel to the skin. In addition, the characteristics of permeation and metabolism of both LX and the trans-OH form were examined by a mathematical pharmacokinetic model. The Km value was calculated to be 10.3 mM in the human in vitro skin. The predominant enzyme which generates the trans-OH form in human whole skin was identified to be carbonyl reductase 1 (CBR1) by immunodepletion using the anti-human CBR1 antibody. The results of the enzyme kinetic study using the recombinant human CBR1 protein demonstrated that the Km and Vmax values were 7.30 mM and 402 nmol/min/mg protein, respectively. In addition, we found that no unknown metabolites were generated in the human in vitro skin. This is the first report where LX is bioactivated to the trans-OH form in human skin by CBR1. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 03/2015; DOI:10.1002/bdd.1945
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    ABSTRACT: Recently, we have found that the carbonyl group of 1-[3-(4-phenoxyphenoxy)-2- oxopropyl]indole-5-carboxylic acid (5), an inhibitor of the pro-inflammatory enzyme cytosolic phospholipase A2 α, is easily reduced by rat liver S9 fractions in vitro. Determination of the inhibitory potency of certain putative inhibitors of carbonyl reducing enzymes on the transformation of the ketone derivative 5 to its alcohol 6 by recombinant microsomal NADPH-cytochrome P450 reductase and by recombinant cytosolic carbonyl reductase-1 now revealed that the compounds applied lack specificity for these two enzymes in part. Thus, an assignment of the roles of different carbonyl reductases in metabolic keto reduction by the use of inhibitors is problematic. Besides, the ability of NADPH-cytochrome P450 reductase and carbonyl reductase-1 to reduce the ketone group of the drugs haloperidol and daunorubicin was examined. Under the conditions applied, a pronounced reductive metabolism was only observed for daunorubicin in presence of microsomal NADPH-cytochrome P450 reductase. Similarly, in rat liver S9 fractions a marked reduction of daunorubicin was seen, while haloperidol was only slightly metabolized to its alcohol. After separation of the S9 homogenate into a microsomal and a cytosolic fraction, it became evident that the ketone groups of daunorubicin, haloperidol and compound 5 were mainly reduced by cytosolic enzymes. However, since microsomes also catalyzed these carbonyl reductions to some extent, it can be concluded that microsomal NADPH-cytochrome P450 reductase can contribute to metabolic keto reductions in xenobiotics. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 03/2015; DOI:10.1002/bdd.1946
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    ABSTRACT: Veratramine, a steroidal alkaloid originated from Veratrum nigrum L., has demonstrated distinct anti-tumor and anti-hypertension effects, however, its metabolism has rarely been explored. The objective of current study is to provide a comprehensive investigation on its metabolic pathways. The in vitro metabolic profiles of veratramine were evaluated by incubating with liver microsomes and cytosols. The in vivo metabolic profiles in plasma, bile, urine and feces were monitored by UPLC-MS/MS after its oral (20 mg/kg) and i.v. (50 µg/kg) administrations in rats. Meanwhile, related P450s inhibitors and recombinant P450s and SULTs were used to identify the isozymes responsible for its metabolism. Eleven metabolites of veratramine, including seven hydroxylated, two sulfated and two glucuronidated metabolites, were characterized. Unlike most of alkaloids, major reactive sites of veratramine were on ring A and B instead of amine moiety. CYP2D6 was the major isozyme mediated hydroxylation and substrate inhibition was observed with a Vmax , Ki and Clint of 2.05 ± 0.53 nmol/min/mg, 33.08 ± 10.13 μM and 13.58 ± 1.27 μL/min/mg. SULT2A1, with Km , Vmax and Clint values of 19.37 ± 0.87 μM, 1.51 ± 0.02 nmol/min/mg and 78.19 ± 8.57 μL/min/mg, was identified as the major isozyme contributed to its sulfation. In conclusion, CYP2D6 and SULT2A1 mediated hydroxylation and sulfation were identified as the major biotransformation for veratramine. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 03/2015; DOI:10.1002/bdd.1942
  • Biopharmaceutics & Drug Disposition 03/2015; 36(2):69-70. DOI:10.1002/bdd.1939
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    ABSTRACT: A new in vitro microfluidic platform(Integrated Insert Dynamic Microfluidic Platform, IIDMP) allowing the coculture of intestinal cells Caco-2 TC7 and of human primary hepatocytes was used to test the absorption and first pass metabolism of two drugs : phenacetin and omeprazole. The metabolism of these drugs by CYP1A2, CYP2C19 and CYP3A4 was evaluated by the calculation of bioavailabilities and of intrinsic clearances using a pharmacokinetic (PK) model. To demonstrate the usefulness of the device and of the PK model, predictions were compared with the in vitro and in vivo results from the literature. Based on the IIDMP experiments, we predicted hepatic in vivo clearances of phenacetin and omeprazole in the IIDMP of 3.10 ± 0.36 and 1.46 ± 0.25ml/min/kg of bodyweight respectively. This appeared lower than in vivo observed data with values ranging between 11.9-19.6 and 5.8-7.5 ml/min/kg of bodyweight respectively. Then, the calculated hepatic and intestinal clearances led to predict oral bioavailability of 0.85 and 0.77 for phenacetin and omeprazole versus 0.92 and 0.78 using separate data of simple monoculture of Caco-2 TC7 and hepatocytes in Petri dishes. When compared to in vivo data, we overestimated the results of oral bioavailability (equal to 0.37 and 0.71 respectively). We demonstrated the feasibility of the coculture in a device allowing the integration of intestinal absorption, intestinal metabolism and hepatic metabolism in a single model. Nevertheless, further experiments with other drugs are needed to extend the knowledge on the device to predict oral bioavailability and intestinal first pass metabolism. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 02/2015; DOI:10.1002/bdd.1940
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    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; DOI:10.1002/bdd.1938
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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; DOI:10.1002/bdd.1937
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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; DOI:10.1002/bdd.1936
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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; DOI:10.1002/bdd.1935
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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; 36(2). DOI:10.1002/bdd.1934
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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; DOI:10.1002/bdd.1933
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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; DOI:10.1002/bdd.1929
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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 03/2015; 36(2). DOI:10.1002/bdd.1925