European Journal of Drug Metabolism and Pharmacokinetics (EUR J DRUG METAB PH)

Publisher: Springer Verlag

Journal description

The European Journal of Drug Metabolism and Pharmacokinetics addresses all aspects of pre-clinical and clinical pharmacokinetics, including drug disposition, drug metabolism, drug transport, drug interactions, bioavailability and biopharmacy. The journal welcomes publications in the field of pharmacokinetic modeling. Analytical methods validation and bioequivalence studies will not be considered for publication. The journal publishes original articles, short preliminary communications, review articles on special topics, and conference proceedings. The European Journal of Drug Metabolism and Pharmacokinetics publishes four issues a year.

Current impact factor: 1.31

Impact Factor Rankings

2015 Impact Factor Available summer 2015
2013 / 2014 Impact Factor 1.312
2012 Impact Factor 0.944
2011 Impact Factor 0.356
2010 Impact Factor 0.353
2009 Impact Factor 0.677
2008 Impact Factor 0.738
2007 Impact Factor 0.565
2006 Impact Factor 0.479
2005 Impact Factor 0.585
2004 Impact Factor 0.447
2003 Impact Factor 0.474
2002 Impact Factor 0.329
2001 Impact Factor 0.392
2000 Impact Factor 0.488
1999 Impact Factor 0.419
1998 Impact Factor 0.556
1997 Impact Factor 0.567
1996 Impact Factor 0.506
1995 Impact Factor 0.604
1994 Impact Factor 0.489
1993 Impact Factor 0.37
1992 Impact Factor 0.723

Impact factor over time

Impact factor

Additional details

5-year impact 0.84
Cited half-life 0.00
Immediacy index 0.30
Eigenfactor 0.00
Article influence 0.19
Website European Journal of Drug Metabolism and Pharmacokinetics website
Other titles European journal of drug metabolism and pharmacokinetics
ISSN 0378-7966
OCLC 2181264
Material type Periodical
Document type Journal / Magazine / Newspaper

Publisher details

Springer Verlag

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  • Classification
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Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Isocorynoxeine (IC), a major alkaloid found in Uncaria rhynchophylla, exhibits wide beneficial effects on the cardiovascular and cardiocerebral vascular systems. Its metabolic pathway, however, has not been well studied yet. In this study, an ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (U-HPLC/Q-TOFMS) method was developed to investigate IC metabolism in plasma, urine and bile in rats given IC orally at 40 mg/kg. Nine male Wistar rats were given IC 40 mg/kg orally. Blood, urine and bile samples were collected at pre-specified times to measure the concentration of IC. A total of 35 metabolites were tentatively identified by the co-chromatography of biosamples and comparison of the retention time, characteristic molecular ions and fragment ions with those of the authentic standards or tentatively identified by MS/MS determination along with MassFragment software. Among them, 18, 33 and 18 metabolites were found in plasma, urine and bile samples, respectively. The relative percentage area of each metabolite was also determined to better understand the major metabolic pathways of IC in rats. The result indicates that IC undergoes extensive metabolism in vivo, mainly including hydrolysis, oxidation, isomerization, demethylation, epoxidation, reduction, glucuronidation, hydroxylation and N-oxidation, which is helpful for the further pharmacokinetic study of IC in vivo.
    European Journal of Drug Metabolism and Pharmacokinetics 06/2015; DOI:10.1007/s13318-015-0287-0
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    ABSTRACT: Methotrexate (MTX) is a disease-modifying anti-rheumatic drug used in the treatment of rheumatoid arthritis (RA). It is the first line drug in the treatment of this disease. However, MTX-related adverse drug reactions (ADRs) are seen in 40 % of the patients. The aim of this study was to determine the impact of six genetic polymorphisms located in five genes encoding proteins involved in the MTX metabolic pathway in Tunisian RA patients and evaluate its association with MTX toxicity. Genotyping of 5,10 methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), dihydrofolate reductase (DHFR 19-base pair deletion allele), thymidylate synthase (TYMS 2R/3R), methionine synthase (MTR A2756G) and methionine synthase reductase (MTRR A66G) was performed using PCR and PCR-RFLP method in 141 RA patients treated with MTX. Demographic and clinical characteristics were obtained and ADRs were recorded. Association analyses with regard to MTX toxicity were performed using the χ (2) test, the toxicogenetic risk index (TRI) and the Mann-Whitney U-test. The analysis highlighted a significant association of the T/T genotype of MTHFR C677T polymorphism with increased MTX toxicity. However, the MTHFR A1298C, DHFR 19-base pair deletion allele, MTR A2756G and MTRR A66G polymorphisms were not associated with increased MTX toxicity. The TYMS 2R/3R polymorphism had a protective effect against MTX toxicity. The results demonstrated that the C677T polymorphism in the MTHFR gene is associated with MTX toxicity in Tunisian RA patients. In contrast, the TYMS 2R/3R polymorphism is associated with a protective effect against overall MTX toxicity.
    European Journal of Drug Metabolism and Pharmacokinetics 06/2015; DOI:10.1007/s13318-015-0288-z
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    ABSTRACT: Nalfurafine hydrochloride (TRK-820), which exhibits strong κ-opioid agonistic activity, has an antipruritic effect on uremic pruritus. The permeability of nalfurafine across human P-glycoprotein (P-gp)-expressing LLC-PK1 cells was investigated to evaluate drug-drug interactions (DDI) involving the P-gp efflux transporter of nalfurafine. Furthermore, we assessed the ratio of brain/plasma concentrations (K p) as an indicator to investigate the changes in the blood-brain barrier (BBB) transport through P-gp when digoxin or verapamil was concomitantly administered with nalfurafine in mice. All samples were analyzed by liquid chromatography-tandem mass spectrometry or a liquid scintillation counter. The cleared volume ratio (cleared volume from basal to apical/cleared volume from apical to basal) of nalfurafine in P-gp-expressing cells was higher than that in the control cells; however, no concentration-dependent decrease in the cleared volume ratio of digoxin was observed in the presence of nalfurafine. The K p value in mice showed similar profiles to those observed with nalfurafine alone and when co-administered with digoxin or verapamil. From these results, nalfurafine was found to be a substrate for P-gp, but had no inhibitory effect on P-gp-mediated transport. Furthermore, it is unlikely that nalfurafine transport via the BBB is affected by P-gp substrates in humans.
    European Journal of Drug Metabolism and Pharmacokinetics 06/2015; DOI:10.1007/s13318-015-0286-1
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    ABSTRACT: α-Mangostin, a major xanthone isolated from the pericarp of Garcinia mangostana, exhibits anti-inflammatory and antitumor effects. Its absolute bioavailability is low, with minimal oral absorption. In this article, a soft capsule, with vegetable oil as the dispersion matrix, was prepared to improve the bioavailability of α-mangostin. Its pharmacokinetics and tissue distribution were determined in rats. An HPLC assay was established to determine the concentration of α-mangostin in biological samples. The validated method was used successfully to support pharmacokinetic and tissue distribution studies of α-mangostin in rats after intravenous (i.v.) and oral administration. The pharmacokinetic study found the absolute bioavailabilities of low, medium and high doses were 61.1, 51.5 and 42.5 %, respectively, indicating that the absolute bioavailability was effectively improved.
    European Journal of Drug Metabolism and Pharmacokinetics 05/2015; DOI:10.1007/s13318-015-0283-4
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    ABSTRACT: Honokiol (HK) is the main bioactive compound isolated from the bark of Magnolia officinalis. The present work is the first to report the pharmacokinetics and distribution of HK and its two metabolites of hydroxylated HK conjugated with glucuronic and sulfuric acid (M1) and HK monoglucuronide (M2) in plasma, liver, kidney and brain following oral administration of HK (40 mg/kg) to healthy Wistar rats. The results showed that only HK but not M1 or M2 was found in brain. Additionally, our work indicated that M2 not HK was the major compound in liver and plasma. The elimination of HK in liver, kidney and brain, and M2 in liver and kidney was more rapid than in plasma. The finding suggested that some of the pharmacological activity of HK might be generated by M2 but not HK.
    European Journal of Drug Metabolism and Pharmacokinetics 05/2015; DOI:10.1007/s13318-015-0281-6
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    ABSTRACT: Currently, macromolecular drugs such as proteins are mainly administered by means of injections due to their low intestinal epithelial permeability and poor stability in the gastrointestinal tract. This study investigated binary combinations of chemical drug absorption enhancers to determine if synergistic drug absorption enhancement effects exist. Aloe vera, Aloe ferox and Aloe marlothii leaf gel materials, as well as with N-trimethyl chitosan chloride (TMC), were combined in different ratios and their effects on the transepithelial electrical resistance (TEER), as well as the transport of FITC-dextran across Caco-2 cell monolayers, were measured. The isobole method was applied to determine the type of interaction that exists between the absorption enhancers combinations. The TEER results showed synergism existed for the combinations between A. vera and A. marlothii, A. marlothii and A. ferox as well as A. vera and TMC. Antagonism interactions also occurred and can probably be explained by chemical reactions between the chemical permeation enhancers, such as complex formation. In terms of FITC-dextran transport, synergism was found for combinations between A. vera and A. marlothii, A. marlothii and A. ferox, A. vera and TMC, A. ferox and TMC and A. marlothii and TMC, whereas antagonism was observed for A. vera and A. ferox. The combinations where synergism was obtained have the potential to be used as effective drug absorption enhancers at lower concentrations compared to the single components.
    European Journal of Drug Metabolism and Pharmacokinetics 05/2015; DOI:10.1007/s13318-015-0280-7
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    ABSTRACT: Use of dietary products is on the rise due to health benefits associated with the ingestion of flavonoids contained in them. Biochanin A (BioA) is the major constituent of red clover extract and has undergone investigations for health benefits and drug interaction potential. In many instances, BioA has exhibited a clear anomaly in the in vivo pharmacokinetics of co-administered drugs which were contrary to the in vitro studies. The focus of this review is to critically evaluate several mechanisms that may come into play for the interpretation of the in vivo pharmacokinetic data of drugs co-administered with BioA.
    European Journal of Drug Metabolism and Pharmacokinetics 04/2015; 40(2). DOI:10.1007/s13318-015-0279-0
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    ABSTRACT: IDX184 is a phosphoramidate prodrug of 2'-methylguanosine-5'-monophosphate, developed to treat patients infected with hepatitis C virus. A mass balance study of radiolabeled IDX184 and pharmacokinetic studies of IDX184 in portal vein-cannulated monkeys revealed relatively low IDX184 absorption but higher exposure of IDX184 in the portal vein than in the systemic circulation, indicating >90 % of the absorbed dose was subject to hepatic extraction. Systemic exposures to the main metabolite, 2'-methylguanosine (2'-MeG), were used as a surrogate for liver levels of the pharmacologically active entity 2'-MeG triphosphate, and accordingly, systemic levels of 2'-MeG in the monkey were used to optimize formulations for further clinical development of IDX184. Capsule formulations of IDX184 delivered acceptable levels of 2'-MeG in humans; however, the encapsulation process introduced low levels of the genotoxic impurity ethylene sulfide (ES), which necessitated formulation optimization. Animal pharmacokinetic data guided the development of a tablet with trace levels of ES and pharmacokinetic performance equal to that of the clinical capsule in the monkey. Under fed conditions in humans, the new tablet formulation showed similar exposure to the capsule used in prior clinical trials.
    European Journal of Drug Metabolism and Pharmacokinetics 04/2015; DOI:10.1007/s13318-015-0267-4
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    ABSTRACT: The study was to establish a population pharmacokinetic (PPK) model of piperacillin (PIP) and tazobactam (TAZ) that explain pharmacokinetic variability and to propose optimized dosage regimens in patients with nosocomial infections. In total, 310 PIP and 280 TAZ concentration-time points were collected at steady state over multiple dosing intervals from 50 patients who received PIP/TAZ infused within 30 min or over 3 h. Drug analysis was performed by high-performance liquid chromatography (HPLC). Nonlinear mixed effects modeling was employed to develop PPK model and 1000 Monte Carlo simulation was used to predict the probability of target attainment (PTA) with a target time of non-protein-bound concentration above MIC > 50 % of the dosing interval. A model with one-compartment model had the best predictive performance for the PPK model. The population estimates of PIP were 13.8 L/h (31.1 %) for clearance (CL) and 21.7 L (38 %) for volume of distribution (V). The population estimates of TAZ were 9.3 L/h (29.1 %) for CL and 16 L (35.3 %) for V. Influence of creatinine clearance (CLcr) and body weight were identified as important covariates for PIP/TAZ CL and V, respectively. A 30-min infusion of 4 g every 6 h achieved robust (≥90 %) PTAs for MIC ≤ 16 mg/L. As an alternative mode of administration, a 3-h infusion of 4 g every 6 h achieved robust PTAs for Pseudomonas aeruginosa and Klebsiella pneumoniae. Prolonged infusions achieved better PTAs compared with shorter infusions at similar daily doses. This benefit was most pronounced for MICs between 16 and 40 mg/L.
    European Journal of Drug Metabolism and Pharmacokinetics 04/2015; DOI:10.1007/s13318-015-0276-3
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    ABSTRACT: Organic cation transporter 2 (rOCT2) and multidrug and toxin extrusion protein 1 (rMATE1) are mainly expressed in rat renal proximal tubules and mediate urinary excretion of cationic drugs, such as metformin. Accumulated evidence indicated that renal rOCT2 expression in male rats is much higher than that of female rats. However, it is unclear whether the gender-related differences in rOCT2 expression between male and female rats can affect the urinary excretion of metformin. The aim of this study was to investigate the effect of gender on the pharmacokinetics of metformin and to clarify the effect of gender-related differences on renal rOCT2 expression and its role in urinary excretion of metformin. Renal rOCT2 levels, but not rOCT1 and rMATE1, were significantly lowered in female rats when compared to that of male rats (P < 0.01), while the pharmacokinetic parameters, i.e., AUC0→t, t 1/2, CL/F, and cumulative urinary excretion of metformin, did not show any significant differences between female and male rats following oral administration of metformin at l00 mg/kg (P > 0.05). However, when metformin was orally administered at the dose of 500 mg/kg, the cumulative urinary excretion and renal tissue-to-plasma concentration ratio of metformin in female rats (26,689 ± 1266 μg and 2.96 ± 0.47 mL/g, respectively) were markedly lowered compared to that of male rats (32,949 ± 1384 μg and 4.20 ± 0.31 mL/g, respectively), and the plasma concentration of metformin in female rats (55.9 ± 4.5 μg/mL) was significantly increased compared to that of male rats (43.5 ± 3.1 μg/mL) at 2 h after oral administration. These results indicated that effect of gender-related differences on renal rOCT2 expression indeed contributes to the decreased urinary excretion of metformin in female rats when metformin was administered at relatively high doses.
    European Journal of Drug Metabolism and Pharmacokinetics 04/2015; DOI:10.1007/s13318-015-0278-1
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    ABSTRACT: Trandolapril is the pro-drug of trandolaprilat, a non-sulfhydryl angiotensin-converting enzyme inhibitor. This study was designed to assess the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of single and multiple doses of trandolapril in healthy Chinese subjects. Healthy subjects (six men and six women) were randomized into a single-dose, 3 × 3 crossover study (1-2-4 mg, 2-4-1 mg, and 4-1-2 mg), and a multiple-dose study (2 mg/day, 6 days). Serial blood and urine samples were collected after drug administration and analyzed using a validated LC-MS/MS method, and the trandolapril and trandolaprilat PK parameters were obtained. PD was evaluated by the changes in blood pressure and heart rates after dosing. Tolerability was assessed by monitoring adverse events, vital signs, ECGs, and changes in laboratory tests. In the single-dose study, trandolapril was absorbed rapidly, and peak plasma levels (C max, 1.57, 3.77, and 7.99 ng/mL) and AUCs (1.89, 3.46, and 6.47 ng/mL) were dose-dependent. The AUC0-∞ of trandolaprilat was dose-dependent, but in a non-linear fashion. The cumulative urine excretion of trandolapril and trandolaprilat was 5.51, 6.20, and 7.41 % for three doses, respectively. In the multiple-dose study, steady-state pharmacokinetics was observed; there was no trandolapril accumulation, but there was mild trandolaprilat accumulation (R = 1.67). Trandolapril was well tolerated. The most pronounced reductions in blood pressure were observed at 8 h after administration, which was later than T max. No orthostatic hypotension occurred. The pharmacokinetics and pharmacodynamics following single and multiple oral doses trandolapril in healthy Chinese subjects are similar to those observed in non-Chinese healthy subjects.
    European Journal of Drug Metabolism and Pharmacokinetics 04/2015; DOI:10.1007/s13318-015-0277-2
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    ABSTRACT: The aim of this study was to investigate the role of P-glycoprotein (P-gp) in the intestinal absorption of triptolide. In this research, the bidirectional transport of triptolide across Caco-2 cells was studied in vitro. Moreover, the pharmacokinetic profiles of orally administered triptolide with and without pretreatment with verapamil were determined in rats. A markedly higher transport of triptolide across Caco-2 cells was observed in the basolateral-to-apical direction and was abrogated in the presence of the P-gp inhibitor, verapamil. The result indicated that P-gp might be involved in the absorption of triptolide. When the rats were pretreated with verapamil, the C max of triptolide increased from 423.01 ± 19.59 to 565.33 ± 20.27 ng/mL (33.6 %), and the AUC0-6 h increased by approximately 57 % when co-administered with verapamil. It was demonstrated that P-gp was involved in the transport of triptolide, which might exhibit a role in limiting its absorption and attenuating the toxicity of triptolide.
    European Journal of Drug Metabolism and Pharmacokinetics 04/2015; DOI:10.1007/s13318-015-0275-4
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    ABSTRACT: Rotigotine is a dopamine receptor agonist indicated for the treatment of Parkinson's disease and moderate-to-severe restless legs syndrome. Continuous transdermal delivery of rotigotine via a silicon-based patch maintains stable plasma concentrations over 24 h. The objective of the study was to evaluate the pharmacokinetics, safety, and tolerability of a multiple-dose schedule of rotigotine transdermal patch in Japanese and Caucasian subjects. In this open-label, repeated-dose, parallel-group study ( NCT01854216), healthy male and female subjects of Japanese or Caucasian ethnic origin were matched by gender, body mass index, and age. Subjects underwent a 9-day patch application period. 12 Japanese and 12 Caucasian subjects were included in the pharmacokinetic analyses. Mean apparent doses (actual amount of drug delivered) increased proportionally with rotigotine nominal dosages (1, 2, and 4 mg/24 h) and were similar for both ethnic groups, with large inter-individual variability. Mean plasma concentration-time profiles for unconjugated rotigotine were similar in both ethnic groups at day 3 for each dosage. Peak concentrations (C max,ss) and area under the concentration-time curves from pre-dose to the concentration measured 24 h after administration of patch (AUC(0-24,ss)) showed similar exposure in both groups; higher values in Japanese subjects were explained by differences in body weight. For total rotigotine, C max,ss and AUC(0-24,ss) values were higher in Caucasian subjects and could be explained by small differences in apparent dose. Rotigotine was generally well tolerated following multiple applications up to 4 mg/24 h. These findings suggest similar dosage requirements for rotigotine transdermal system in Japanese and Caucasian populations.
    European Journal of Drug Metabolism and Pharmacokinetics 03/2015; DOI:10.1007/s13318-015-0273-6
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    ABSTRACT: This study developed a physiologically based pharmacokinetic (PBPK) model in intraabdominally infected rats and extrapolated it to humans to predict the levofloxacin pharmacokinetics and penetration into tissues. Twelve male rats with intraabdominal infections induced by Escherichia coli received a single dose of 50 mg/kg body weight of levofloxacin. Blood plasma was collected at 5, 10, 20, 30, 60, 120, 240, 480 and 1440 min after injection, respectively. A PBPK model was developed in rats and extrapolated to humans using GastroPlus software. The predictions were assessed by comparing predictions and observations. In the plasma concentration-versus-time profile of levofloxacin in rats, C max was 23.570 μg/ml at 5 min after intravenous injection, and t1/2 was 2.38 h. The plasma concentration and kinetics in humans were predicted and validated by the observed data. Levofloxacin penetrated and accumulated with high concentrations in the heart, liver, kidney, spleen, muscle and skin tissues in humans. The predicted tissue-to-plasma concentration ratios in abdominal viscera were between 1.9 and 2.3. When rat plasma concentrations were known, extrapolation of a PBPK model was a method to predict the drug pharmacokinetics and penetration in humans. Levofloxacin had good penetration into the liver, kidney and spleen as well as other tissues in humans. This pathological model extrapolation may provide a reference for the study of antiinfective PK/PD. In our study, levofloxacin penetrated well into abdominal organs. Also ADR monitoring should be implemented when using levofloxacin.
    European Journal of Drug Metabolism and Pharmacokinetics 03/2015; DOI:10.1007/s13318-015-0271-8
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    ABSTRACT: Pogostemonis herba is used in traditional Chinese medicine to remove dampness, relieve sunstroke, stop vomiting and increase appetite. Patchouli alcohol, an ingredient in pogostemonis herba, has the potential to treat inflammation as well as bacterial and fungal infections. The essential oil of pogostemonis herba (patchouli oil) is commonly given orally in clinical settings; however, no pharmacokinetic studies have examined its oral administration. The goal of this study was to investigate the pharmacokinetic behavior of patchouli alcohol following single-dose oral administration in rats; the influence of other patchouli oil components on the pharmacokinetic profile of patchouli alcohol was also examined. In this study, a simple and selective GC/MS method was developed and validated to measure the level of patchouli alcohol in rat plasma. The study revealed that the pharmacokinetics profile was linear in both the patchouli alcohol and patchouli oil groups. The C max and AUC0-t of patchouli alcohol were greater in all three doses of patchouli alcohol compared to corresponding patchouli oil doses. Additionally, the T max values were significantly greater in the patchouli oil group. These results suggest that the other ingredients in patchouli oil influence the pharmacokinetic behavior of patchouli alcohol during its absorption. The results provide a meaningful basis for evaluating the clinical application of patchouli oil and patchouli alcohol.
    European Journal of Drug Metabolism and Pharmacokinetics 03/2015; DOI:10.1007/s13318-015-0272-7
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    ABSTRACT: Metabolism-mediated drug adverse effects (e.g., drug–drug interaction, bioactivation, etc.) strongly limit the utilization of clinical drugs. The present study aims to predict the metabolic capability of cytochrome P450 (CYP) 3A4 toward pazopanib which is an excellent drug exhibiting therapeutic role toward various cancers especially for ovarian cancer. Pazopanib can be well docked into the activity cavity of CYP3A4, and the interaction structure in pazopanib was methyl group located besides nitrogen in the five-membered ring. The distance between the hydrogen atom in methyl group and active center is 3.64 Å. The interaction amino acid is Glu374. Furthermore, both pazopanib and ketoconazole were docked into the activity cavity of CYP3A4 to compare their binding potential. The distance between ketoconazole and activity center (2.10 Å) is closer than the distance between pazopanib and activity center of CYP3A4, indicating the easy influence of CYP3A4 inhibitor toward the metabolism of pazopanib. All these data were helpful for the clinical application of pazopanib, and R&D of other tinib drug candidates as new anti-tumor drugs.
    European Journal of Drug Metabolism and Pharmacokinetics 03/2015; DOI:10.1007/s13318-015-0252-y
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    ABSTRACT: Etanercept was approved by the Food and Drug Administration (FDA) in 2010 as a biologic agent for the treatment of rheumatoid arthritis (RA). The aim of the study was to investigate the pharmacokinetic properties of etanercept after intravenous and subcutaneous injection in rats. The plasma concentration of etanercept was determined using an enzyme-linked immunosorbent assay (ELISA). Intravenous and subcutaneous administration of 2 mg/kg of etanercept to rats showed that etanercept was slowly absorbed (time to reach the peak drug concentration [T max] = 1.60 days, bioavailability [F] = 47.18 %) and slowly eliminated (half-life [t 1/2], 2.33 days after intravenous administration and 3.31 days after subcutaneous administration). The area under the curve values on day 13 (AUC13day) were 121.25 ± 14.37 and 48.56 ± 6.78 μg day/mL after intravenous and subcutaneous administration, respectively. A two-compartment model with Michaelis-Menten elimination kinetics (V max = 94.28 µg/day; K m = 10.88 µg/mL) was used to describe the pharmacokinetic profile of etanercept. Our results describe the pharmacokinetic profile of etanercept, and these results could be used for the development of etanercept biosimilars.
    European Journal of Drug Metabolism and Pharmacokinetics 03/2015; DOI:10.1007/s13318-015-0270-9
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    ABSTRACT: Previous in vitro and in vivo investigations reported controversial results for the inhibitory potential of pomegranate on Cytochrome P450 (CYP) 3A activity. This study evaluated the effect of pomegranate juice on the disposition of simvastatin, a CYP3A4 substrate, and simvastatin acid, its active metabolite, compared with grapefruit juice in healthy subjects. A single oral pharmacokinetic study of 40 mg simvastatin was conducted as a three-way crossover (control, pomegranate, and grapefruit juices) in 12 healthy male subjects. The subjects took pomegranate or grapefruit juice three times per day for 3 days (900 mL/day) and on the third day, the pharmacokinetic study was executed. Blood samples were collected to 24 h post-dose and the pharmacokinetic parameters of simvastatin and simvastatin acid were compared among the study periods. In the period of grapefruit juice, the mean C max and AUCinf of simvastatin [the geometric mean ratio (90 % CI) 15.6 (11.6-21.0) and 9.1 (6.0-13.7)] were increased significantly when compared with the control period, whereas they were not significantly different in the period of pomegranate juice [C max and AUCinf 1.20 (0.89-1.62) and 1.29 (0.85-1.94)]. The mean C max and AUCinf of simvastatin acid were increased significantly after intake of grapefruit juice, but not pomegranate juice. These results suggest that pomegranate juice affects little on the disposition of simvastatin in humans. Pomegranate juice does not seem to have a clinically relevant inhibitory potential on CYP3A4 activity.
    European Journal of Drug Metabolism and Pharmacokinetics 02/2015; DOI:10.1007/s13318-015-0263-8