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
2007 Impact Factor 1.238
2006 Impact Factor 1.152
2005 Impact Factor 1.11
2004 Impact Factor 1.068
2003 Impact Factor 1.763
2002 Impact Factor 0.688
2001 Impact Factor 0.772
2000 Impact Factor 0.819
1999 Impact Factor 1.068
1998 Impact Factor 0.789
1997 Impact Factor 0.802
1996 Impact Factor 0.824
1995 Impact Factor 0.737
1994 Impact Factor 0.809
1993 Impact Factor 0.609
1992 Impact Factor 0.595

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
    • Author can archive a pre-print version
  • Post-print
    • Author cannot archive a post-print version
  • Restrictions
    • 12 months embargo
  • Conditions
    • Some journals have separate policies, please check with each journal directly
    • 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
    • Author's pre-print must acknowledge acceptance for publication
    • On a non-profit server
    • Publisher's version/PDF cannot be used
    • 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: Mefenamic acid (MEF) is a widely prescribed non-steroidal anti-inflammatory drug that has been found associated with rare but severe cases of hepatotoxicity, nephrotoxicity and gastrointestinal toxicity. Formation of protein-reactive acylating metabolites such as 1-O-acyl-MEF glucuronide (MEFG) and 3'-hydroxymethyl-MEF 1-O-acyl-glucuronide is one proposed cause. In addition to the well-reported 3'-hydroxymethyl-MEF, two mono-hydroxyl-MEF (OH-MEFs) were recently identified in vitro. However, in vivo evidence and whether these OH-MEFs would be further glucuronidated to the potentially reactive 1-O-acyl-glucuronides (OH-MEFGs) is lacking. Utilizing UPLC-Q-TOF/MS and LC-MS/MS, the current study for the first time identified four OH-MEFs and their corresponding OH-MEFGs from plasma after single oral MEF (40 mg/kg) administration to rats, including an OH-MEF that has not been previously reported. The systemic exposure of these identified metabolites was high, with metabolic to parent AUC0→24h ratios reaching 23-52% (OH-MEFs) and 8-29% (OH-MEFGs). These metabolites also had long systemic exposure time in both single and 5-day multiple oral MEF-treated rats, with elimination half-lives between 9 h and >24 h. In addition to these novel metabolites, the previously reported MEFG was also identified and its systemic exposure was found to be doubled after multiple MEF administrations. These pharmacokinetic results suggest that systemic toxicities caused by the potentially reactive MEFG and OH-MEFGs could be considerable, especially after repeated MEF treatment. Nevertheless, MEFG and OH-MEFGs had negligible brain uptakes, indicating minimal risk of brain toxicities. Furthermore, in situ intestinal perfusion study revealed that during MEF absorption, it was extensively metabolized to MEFG while <5% was metabolized to OH-MEFs and OH-MEFGs. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 06/2015; DOI:10.1002/bdd.1964
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    ABSTRACT: Protein phosphorylation is a vital posttranslational modification. In this study, we investigated the effect of phosphorylation on human uridine diphosphate (UDP)-glucuronosyltransferase 1A3 (UGT1A3) activity. Curcumin and calphostin C suppressed the activity and phosphorylation of recombinant UGT1A3 expressed in Sf9 cells. These results indicate that UGT1A3 undergoes phosphorylation, which is required for its catalytic activity. Calphostin C is a highly specific protein kinase C (PKC) inhibitor, so we examined three predicted PKC phosphorylationsites inUGT1A3. Site-directed mutation analysis at residues 28, 43, and 436 (from serine to glycine) was conducted. Compared with the wild-type, the S43G-mutant showed significantly decreased UGT1A3 catalytic activity. Furthermore, the UGT1A3 activity of wild-type and S43G-mutant was downregulated by calphostin C, whereas the calphostin C inhibitory effect was much weaker on S43G-mutant than wild-type. In conclusion, phosphorylation plays an important role in UGT1A3 activity, and the serine at site 43 in UGT1A3 is most likely a phosphorylation site. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 06/2015; DOI:10.1002/bdd.1963
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    ABSTRACT: 4-{(R)-(3-aminophenyl)[4-(4-fluorobenzyl)-piperazin-1-yl]methyl}-N,N-diethylbenzamide (AZD2327) is a highly potent and selective agonist of the δ-opioid receptor. AZD2327 and N-deethylated AZD2327 (M1) are substrates of cytochrome P450 3A (CYP3A4) and comprise a complex multiple inhibitory system that causes competitive and time-dependent inhibition of CYP3A4. The aim of current work was to develop a physiologically based pharmacokinetic (PBPK) model to quantitatively predict the magnitude of CYP3A4 mediated drug-drug interaction with midazolam as the substrate. Integrating in silico, in vitro, and in vivo PK data, a PBPK model was successfully developed to simulate clinical accumulation of AZD2327 and its primary metabolite. The inhibition of CYP3A4 by AZD2327, using midazolam as a probe drug, was reasonably predicted. The predicted maximum concentration (Cmax ) and area under the concentration-time curve (AUC) for midazolam were increased by 1.75 and 2.45-fold, respectively, after multiple dosing of AZD2327, indicating no or low risk for clinical relevant drug-drug interactions (DDI). These results are in agreement with those obtained in a clinical trial of 1.4 and 1.5-fold increase in Cmax and AUC of midazolam, respectively. In conclusion, this model simulated DDI with less than two-fold error, indicating that complex clinical DDI associated with multiple mechanisms, pathways, and inhibitors (parent and metabolite) can be predicted using well developed PBPK model. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 06/2015; DOI:10.1002/bdd.1962
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    ABSTRACT: We evaluated the effect of hypothermia on the in vivo pharmacokinetics of midazolam (MDZ), with a focus on altered metabolism in the liver and binding to serum proteins. Rat primary hepatocytes were incubated with MDZ (which is metabolized mainly by CYP3A2) at 37, 32, or 28 °C. The Michaelis-Menten constant (Km ) and maximum velocity (Vmax ) of MDZ were estimated using the Michaelis-Menten equation. The Km of CYP3A2 MDZ remained unchanged, but the Vmax decreased at 28 °C. In rats, whose temperature was maintained at 37, 32, or 28 °C by a heat lamp or ice pack, plasma concentrations of MDZ were higher, whereas those in the brain and liver were unchanged at 28 °C. Tissue/plasma concentration ratios were, however, increased significantly. The unbound fraction of MDZ in serum at 28 °C was half that at 37 °C. These pharmacokinetic changes associated with hypothermic conditions were due to reductions in CYP3A2 activity and protein binding. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 06/2015; DOI:10.1002/bdd.1960
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    ABSTRACT: The current study was designed to cross-validate rat liver microsomes (RLM), suspended rat hepatocytes (SRH) and the isolated perfused rat liver (IPRL) model against in vivo pharmacokinetic data, using verapamil as a model drug. Michaelis-Menten constants (Km), for metabolic disappearance kinetics of verapamil in RLM and SRH (freshly-isolated and cryopreserved), were determined and corrected for non-specific binding. The "unbound" Km determined with RLM (2.8 μM) was divided by the "unbound" Km determined with fresh and cryopreserved SRH (3.9 μM and 2.1 μM, respectively) to calculate the ratio of intracellular to extracellular unbound concentration (Kpu,u ). Kpu,u was significantly different between freshly-isolated (0.71) and cryopreserved (1.31) SRH, but intracellular capacity for verapamil metabolism was maintained after cryopreservation (200 vs. 191 µl/min/million cells). Direct comparison of intrinsic clearance values (Clint ) in RLM versus SRH, yielded an activity-based scaling factor (SF) of 0.28-0.30 mg microsomal protein/million cells (MPPMC). Merging the IPRL-derived Clint with MPPMC and SRH data, resulted in SFs for MPPGL (80 and 43 mg microsomal protein/g liver) and HPGL (269 and 153 million cells/g liver), respectively. Likewise, the hepatic blood flow (61 ml/min/kg b.wt.) was calculated using IPRL Clint and the in vivo Cl. SFs determined here are consistent with previously reported CYP450-content based SFs. Overall, our results show that integrated interpretation of data obtained with multiple preclinical tools (i.e. RLM, SRH, IPRL) can contribute to more reliable estimates for scaling factors and ultimately to improved in vivo clearance predictions based on in vitro experimentation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 05/2015; DOI:10.1002/bdd.1959
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    ABSTRACT: Pradigastat, a diacylglycerol acyltransferase 1 inhibitor, is being developed for the treatment of the familial chylomicronemia syndrome. We present the results of two studies that evaluated the effect of food on the oral bioavailability of pradigastat using randomized, open-label, parallel group designs in healthy subjects (N = 24/treatment/study). In study 1, a single dose of 20 mg pradigastat was administered under fasted condition or with a high-fat meal. In study 2, a single dose of 40 mg pradigastat was administered under fasted condition or with a low- or high-fat meal. At the 20 mg dose, pradigastat Cmax and AUClast increased by 38% and 41%, respectively, with a high-fat meal. When 40 mg pradigastat was administered with a low-fat meal, Cmax and AUClast increased by 8% and 18%, respectively, whereas with a high-fat meal the increase was 20% and 18%, respectively. The population pharmacokinetic analysis with pooled data of 13 studies indicated that administration of pradigastat with a meal resulted in an increase of 30% in both Cmax and AUC parameters. Based on these results, food overall increased pradigastat exposure in the range of less than 40%, which is not considered clinically significant. Both 20 and 40 mg doses of pradigastat were well tolerated under fasted or fed conditions. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 05/2015; DOI:10.1002/bdd.1958
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    ABSTRACT: Antibody Drug conjugates (ADCs) are a rapidly growing therapeutic platform for the treatment of cancer. ADCs consist of a cytotoxic small molecule drug linked to an antibody to provide targeted delivery of the cytotoxic agent to the tumor. Understanding of the pharmacokinetics (PK) and pharmacodynamics (PD) of ADCs is crucial in their design to optimize dose and regimen, to maximize efficacy and minimize toxicity in patients. Significant progress has been made in recent years in this area, however many fundamental questions still remain. This review discusses factors to consider while assessing disposition of ADCs, and the unique challenges associated with these therapeutics. Current tools that are available and strategies to enable appropriate assessment are also discussed. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 04/2015; DOI:10.1002/bdd.1957
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    ABSTRACT: Betahistine, a potent histamine H3 receptor antagonist, is being developed for the treatment of attention deficit hyperactivity disorder (ADHD) that manifests with symptoms such as hyperactivity, impulsivity and inattention. We describe here the pharmacokinetics of betahistine in ADHD subjects at doses higher than 50 mg. These assessments were made during a randomized, placebo-controlled, single blind, dose escalation study to determine the safety, tolerability and pharmacokinetics of once daily doses 50 mg, 100 mg and 200 mg of betahistine in subjects with ADHD. Plasma levels of 2-pyridylacetic acid (2-PAA), a major metabolite of betahistine were quantified using a validated LC-MS/MS method and used for pharmacokinetic analysis and dose proportionality of betahistine. A linear relationship was observed in Cmax and AUC0-4 of 2-PAA with betahistine dose (R(2) -0.9989 and 0.9978, respectively) and dose proportionality coefficients (β) for power model were 0.8684 (Cmax ) and 1.007 (AUC0-4 ). A population pharmacokinetic model with first order absorption of betahistine and metabolism to 2-PAA, followed by a first order elimination of 2-PAA provides estimates of clearance which underscored the linear increase in systemic exposure with dose. There were no serious adverse events reported in the study, betahistine was safe and well tolerated at all the dose levels tested. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 04/2015; DOI:10.1002/bdd.1955
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    ABSTRACT: The pharmacokinetics of lobeglitazone (LB) was studied after intravenous administration of a dose at 1 mg/kg and oral administration of doses at 0.1, 1 and 10 mg/kg in male and female rats. The area under the plasma concentration-time curve from time zero to infinity (AUCinf ) after intravenous administration was approximately 7.1 times higher in female rats than in male rats. In addition, the AUCinf in the case of oral administration was at least 4.4 times higher in female rats and appeared to increase in proportion to the dose in both genders. The in vitro half-lives were 18.8 ± 4.45 min and 60.7 ± 11.2 min, as evidenced by incubating liver microsomes obtained from male and female rats, respectively. As a result, the estimated CLint for LB for male rat liver microsomes (0.0779 ± 0.0233 mL/min/mg protein) was much higher than that for female rat liver microsomes (0.0233 ± 0.0039 mL/min/mg protein, p < 0.05). These observations suggest that there are gender differences in the pharmacokinetics and hepatic metabolism for LB in rats. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 04/2015; DOI:10.1002/bdd.1954
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    ABSTRACT: Apigenin (API) and Luteolin (LUT) have been used as therapeutic agents in folk medicine for thousands of years. These compounds exert a variety of biological activities, including anti-cancer, anti-oxidant, and anti-inflammatory activities. In this study, we investigated whether API and LUT could activate Nrf2-antioxidant response element (ARE)-mediated gene expression and induce anti-inflammatory activities in human hepatoma HepG2 cells. The compounds did not exhibit any substantial toxicity at low doses (1.56-6.25 μM). We assessed the induction of ARE activity in HepG2-C8 cells after treatment with low doses of API and LUT for 6 and 12 h. We found that the induction of ARE activity by these compounds at the higher doses was comparable to the effects of the positive control, SFN at a dose of 6.25 μM. Exposure to the PI3K inhibitor LY294002 abolished ARE activation by both API and LUT, whereas the ERK-1/2 inhibitor PD98059 only decreased ARE activity induced by API. Both compounds significantly increased the endogenous mRNA and protein levels of Nrf2 and Nrf2 target genes with important effects on heme oxygenase-1 (HO-1) expression. API and LUT significantly and dose-dependently decreased the production of nitric oxide (NO), nitric oxide synthase (iNOS), and cytosolic phospholipase A2 (cPLA2), which were induced by the treatment of HepG2 cells with 1 µg/ml of lipopolysaccharide (LPS) for 24 h. Our results indicate that API and LUT significantly activate the PI3K/Nrf2/ARE system, and this activation may be responsible for their anti-inflammatory effects, as demonstrated by the suppression of LPS-induced NO, iNOS, and cPLA2. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 04/2015; DOI:10.1002/bdd.1956
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    ABSTRACT: Currently, more than 350 monoclonal antibodies (mAbs) and mAb derivatives are under development as therapeutics. The prediction of mAb pharmacokinetics (PK)/pharmacodynamics (PD) plays a key role in starting dose selection for first-in-human (FIH) studies. This article presents a brief overview of the biology and mechanisms of absorption, distribution, metabolism and excretion (ADME) for mAbs. Additionally, we provide a detailed review of mAb human PK/PD prediction from nonclinical data, including allometry for mAbs with linear or nonlinear PK, species-invariant time method, physiologically based PK (PBPK) modeling and target-mediated drug disposition (TMDD) model, bioavailability projection and immunogenicity impact on PK prediction. Finally, from an industry perspective a decision tree of mAb human PK projection is proposed to facilitate drug development. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 04/2015; DOI:10.1002/bdd.1952
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    ABSTRACT: CD70 is a tumor necrosis factor (TNF)-like type II integral membrane protein that is transiently expressed on activated T- and B-lymphocytes. Aberrant expression of CD70 was identified in both solid tumors and haematologic malignancies. BMS-936561 (αCD70_MED-A) is an antibody-drug conjugate composed of a fully human anti-CD70 monoclonal antibody (αCD70) conjugated with a duocarmycin derivative, MED-A, through a maleimide-containing citrulline-valine dipeptide linker. MED-A is a carbamate prodrug that is activated by carboxylesterase to its active form, MED-B, to exert its DNA alkylation activity. In vitro serum stability studies suggested the efficiencies of hydrolyzing the carbamate-protecting group in αCD70_MED-A followed a rank order of mouse > rat > monkey > dog ~ human. Pharmacokinetics of αCD70_MED-A was evaluated in mice, monkeys, and dogs after single intravenous doses. In mice, αCD70_MED-A was cleared rapidly, with no detectable exposures after 15 min following dosing. In contrast, αCD70_MED-A was much more stable in monkeys and dogs. The clearance of αCD70_MED-A in monkeys was 58 mL/d/kg, ~2-fold faster than that in dogs (31 mL/d/kg). The human PK profiles of the total αCD70 and αCD70_MED-A were predicted using allometrically scaled monkeys PK parameters of αCD70 and the carbamate hydrolysis rate constant estimated in dogs. Comparing the predicted and observed human PK from the phase I study, the dose-normalized concentration-time profiles of αCD70_MED-A and the total αCD70 were largely within the 5(th) -95(th) percentile of the predicted profiles. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 04/2015; DOI:10.1002/bdd.1953
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    ABSTRACT: The regression limited sampling strategy approach (R-LSS), which is based on a small number of blood samples drawn at selected time points, has been used as an alternative method for the estimation of the area under the concentration-time curve (AUC). However, deviations from planned sampling times may affect the performance of R-LSS, influencing related therapeutic decisions and outcomes. The aim of this study was to investigate the impact of different sampling time deviation (STD) scenarios on the estimation of AUC by R-LSS using a simulation approach. Three types of scenarios were considered going from the simplest case of fixed deviations, to random deviations and then to a more realistic case where deviations of mixed nature can occur. In addition, the sensitivity of R-LSS to STD in each involved sampling point was evaluated. A significant impact of STD on the performance of R-LSS was demonstrated. The tolerance of R-LSS to STD was found to depend not only on the number of sampling points but more importantly on the duration of the sampling process. Sensitivity analysis showed that sampling points at which rapid concentration changes occur were relatively more critical for AUC prediction by R-LSS. As a practical approach, nomograms were proposed, where the expected predictive performance of R-LSS was provided as a function of STD information. The investigation of STD impact on the predictive performance of R-LSS is a critical element and should be routinely performed to guide R-LSS selection and use. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 04/2015; DOI:10.1002/bdd.1951
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    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: 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: 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
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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: 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