1,109 results match your criteria Drug Metabolism and Pharmacokinetics [Journal]


Appreciation to Reviewers 2018.

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Drug Metab Pharmacokinet 2019 Feb;34(1)

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http://dx.doi.org/10.1016/S1347-4367(19)30027-8DOI Listing
February 2019

Antibody-based therapeutics.

Drug Metab Pharmacokinet 2019 Feb;34(1):1-2

Yokohama University of Pharmacy, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.dmpk.2019.01.006DOI Listing
February 2019

Sulfate conjugates are the major metabolites in rats administrated with sesamin.

Drug Metab Pharmacokinet 2018 Dec 31. Epub 2018 Dec 31.

Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama 939-0398, Japan. Electronic address:

Sesamin is known to have various biological effects. Although several metabolites of sesamin have been identified, its metabolism by phase II enzymes remains unclear, because usually its sulfo- and glucurono-conjugates in plasma and urine are analyzed after sulfatase/β-glucuronidase treatment. In this study, the metabolites of sesamin in rats administrated with sesamin (100 mg/kg b. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.12.004DOI Listing
December 2018

Minimal contribution of P-gp on the low brain distribution of naldemedine, a peripherally acting μ-opioid receptor antagonist.

Drug Metab Pharmacokinet 2018 Dec 23. Epub 2018 Dec 23.

Research Laboratory for Development, Shionogi & Co., Ltd., Japan.

Naldemedine tosylate, a peripherally acting μ-opioid receptor antagonist, is indicated for treatment of opioid induced constipation in both Japan and US. Naldemedine has limited ability to affect the central analgesic effect of opioid analgesics. In this study, we investigated the contribution of P-glycoprotein (P-gp) on the brain distribution of naldemedine. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.12.002DOI Listing
December 2018

Establishment of rat liver microsome-hydrogel system for in vitro phase II metabolism and its application to study pharmacological effects of UGT substrates.

Drug Metab Pharmacokinet 2019 Jan 30. Epub 2019 Jan 30.

School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address:

Studies on the efficacy evaluation of UDP-glucuronosyltransferases (UGTs) substrates often ignore the existence of active metabolites. However, the present study aims to establish an in-vitro Phase II metabolism system to predict their pharmacological effects after metabolism. Rat liver microsomes (RLMs) encapsulated in a F127'-Acr-Bis (FAB) hydrogel were placed in the incubation system. Read More

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http://dx.doi.org/10.1016/j.dmpk.2019.01.005DOI Listing
January 2019

A letter of reply to the commentary by Dr. Stamp et al.

Authors:
Kimiyoshi Ichida

Drug Metab Pharmacokinet 2019 Feb 15;34(1):111-112. Epub 2018 Dec 15.

Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.dmpk.2018.12.001DOI Listing
February 2019

Reconstitution of CYP3A4 active site through assembly of ligand interactions as a grid-template: Solving the modes of the metabolism and inhibition.

Drug Metab Pharmacokinet 2018 Oct 15. Epub 2018 Oct 15.

Regulatory Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.

A hexagonal-grid based template system has been developed to a predicting tool of CYP3A4-mediated reactions through the reconstitution of the active site with the assembly of the ligands. Simultaneous interactions of flattened-shape ligands at two sites of CYP3A4, oxidizing- and triggering-sites, are essential ideas, which were supported in the simulation results of various ligands on the template. The interactions were accomplished with either uni-molecule bindings or bi-molecule bindings with ligands termed pro-metabolized and trigger molecules. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.10.001DOI Listing
October 2018
1 Read

Therapeutic drug monitoring of monoclonal antibodies: Applicability based on their pharmacokinetic properties.

Authors:
Chiyo K Imamura

Drug Metab Pharmacokinet 2019 Feb 7;34(1):14-18. Epub 2018 Dec 7.

Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. Electronic address:

Monoclonal antibodies (mAbs) have dramatically improved clinical outcomes for inflammatory and malignant diseases. The elimination route of mAbs is cellular uptake by nonspecific pinocytosis or receptor-mediated endocytosis followed by proteolytic degradation which is protected by neonatal Fc-receptor or mediated by antigenic target. There is a wide-interindividual variability in mAbs exposure due to target burden and other factors affecting unique their pharmacokinetics. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S13474367183041
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http://dx.doi.org/10.1016/j.dmpk.2018.11.003DOI Listing
February 2019
17 Reads

Biosimilarity assessment of biosimilar therapeutic monoclonal antibodies.

Drug Metab Pharmacokinet 2019 Feb 7;34(1):64-70. Epub 2018 Dec 7.

Yokohama University of Pharmacy, Japan.

The concept of biosimilar was established in the early 2000s in EU. Currently, the regulatory framework for biosimilar has also been established in the US, Japan, and other countries. As of 2018, biosimilars for infliximab, adalimumab, rituximab, trastuzumab, and bevacizumab have been approved. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.11.004DOI Listing
February 2019
4 Reads

Transport of 2,4-dichloro phenoxyacetic acid by human Na-coupled monocarboxylate transporter 1 (hSMCT1, SLC5A8).

Drug Metab Pharmacokinet 2019 Feb 8;34(1):95-103. Epub 2018 Nov 8.

Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba, 274-8510, Japan. Electronic address:

Using X. laevis oocyte expression system, we investigated whether human Na-coupled monocarboxylate transporter 1 (SLC5A8, hSMCT1) is involved in 2,4-dichlorophenoxyacetate (2,4-D) uptake by the renal tubular epithelial cells. 2,4-D is a herbicide that causes nephrotoxicity. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S13474367183013
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http://dx.doi.org/10.1016/j.dmpk.2018.10.004DOI Listing
February 2019
4 Reads

Pharmacokinetics of protein and peptide conjugates.

Drug Metab Pharmacokinet 2019 Feb 22;34(1):42-54. Epub 2018 Nov 22.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, USA. Electronic address:

Protein and peptide conjugates have become an important component of therapeutic and diagnostic medicine. These conjugates are primarily designed to improve pharmacokinetics (PK) of those therapeutic or imaging agents, which do not possess optimal disposition characteristics. In this review we have summarized preclinical and clinical PK of diverse protein and peptide conjugates, and have showcased how different conjugation approaches are used to obtain the desired PK. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S13474367183044
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http://dx.doi.org/10.1016/j.dmpk.2018.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378135PMC
February 2019
8 Reads

Physiologically-based modeling of monoclonal antibody pharmacokinetics in drug discovery and development.

Drug Metab Pharmacokinet 2019 Feb 22;34(1):3-13. Epub 2018 Nov 22.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, 14214 United States. Electronic address:

Over the past few decades, monoclonal antibodies (mAbs) have become one of the most important and fastest growing classes of therapeutic molecules, with applications in a wide variety of disease areas. As such, understanding of the determinants of mAb pharmacokinetic (PK) processes (absorption, distribution, metabolism, and elimination) is crucial in developing safe and efficacious therapeutics. In the present review, we discuss the use of physiologically-based pharmacokinetic (PBPK) models as an approach to characterize the in vivo behavior of mAbs, in the context of the key PK processes that should be considered in these models. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378116PMC
February 2019
2 Reads

Investigation of non-linear Mate1-mediated efflux of trimethoprim in the mouse kidney as the mechanism underlying drug-drug interactions between trimethoprim and organic cations in the kidney.

Drug Metab Pharmacokinet 2019 Feb 20;34(1):87-94. Epub 2018 Sep 20.

Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan. Electronic address:

The purpose of this study was to elucidate the involvement of Mate1 in the tubular secretion of trimethoprim and saturation of Mate1-mediated efflux to address the mechanisms underlying the pharmacokinetic drug interactions with trimethoprim. Trimethoprim is a more potent inhibitor of MATE2-K than MATE1 with K values (μM) of 0.030-0. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.08.005DOI Listing
February 2019
1 Read

Effect of OATP1B1 genotypes on plasma concentrations of endogenous OATP1B1 substrates and drugs, and their association in healthy volunteers.

Drug Metab Pharmacokinet 2019 Feb 20;34(1):78-86. Epub 2018 Sep 20.

Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan. Electronic address:

This study aimed to elucidate the impact of OATP1B1 genotype (*1b/*1b, *1b/*15, and *15/*15) on plasma concentrations of endogenous OATP1B1 substrates. Healthy volunteers with OATP1B1 *1b/*1b (n = 10), *1b/*15 (n = 7), or *15/*15 (n = 2) received oral administration of a cocktail of statins (atorvastatin, pitavastatin, rosuvastatin, and fluvastatin). Mean area under the plasma concentration of atorvastatin, pitavastatin, and rosuvastatin in OATP1B1 *15/*15 were 2. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.09.003DOI Listing
February 2019
1 Read

Improvement of pharmacokinetic properties of therapeutic antibodies by antibody engineering.

Drug Metab Pharmacokinet 2019 Feb 1;34(1):25-41. Epub 2018 Nov 1.

Research Division, Chugai Pharmaceutical Co. Ltd., Gotemba, Japan; Chugai Pharmabody Research Pte. Ltd., Singapore.

Monoclonal antibodies (mAbs) have become an important therapeutic option for several diseases. Since several mAbs have shown promising efficacy in clinic, the competition to develop mAbs has become severe. In efforts to gain a competitive advantage over other mAbs and provide significant benefits to patients, innovations in antibody engineering have aimed at improving the pharmacokinetic properties of mAbs. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S13474367183011
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http://dx.doi.org/10.1016/j.dmpk.2018.10.003DOI Listing
February 2019
16 Reads

Non-synonymous genetic variants of flavin-containing monooxygenase 3 (FMO3) in cynomolgus macaques.

Drug Metab Pharmacokinet 2019 Feb 7;34(1):104-107. Epub 2018 Sep 7.

Showa Pharmaceutical University, Machida, Japan. Electronic address:

Polymorphic human flavin-containing monooxygenase (FMO) 3 is an important drug-metabolizing enzyme for nitrogen- or sulfur-containing compounds. Cynomolgus macaques, a non-human primate species widely used in drug metabolism studies, have corresponding FMO3 molecular and enzymatic similarities to humans; however, genetic polymorphisms have not been investigated in macaques. In this study, re-sequencing of FMO3 in 64 cynomolgus and 32 rhesus macaques found a total of 18 non-synonymous variants. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S13474367183013
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http://dx.doi.org/10.1016/j.dmpk.2018.09.001DOI Listing
February 2019
11 Reads

The extent of drug-drug interaction between amlodipine and activated charcoal is attenuated by food intake in rats.

Drug Metab Pharmacokinet 2019 Feb 28;34(1):108-110. Epub 2018 Aug 28.

Division of Clinical Pharmacokinetics, Keio University Faculty of Pharmacy, 1-5-30, Shibakoen Minato-ku, Tokyo, 105-8512, Japan. Electronic address:

Activated charcoal decreases gastrointestinal absorption of concomitantly administered drugs. The absorption of amlodipine (AML) was reported as almost completely attenuated by 25 g of activated charcoal under a fasted condition, but not affected by 2 g of activated charcoal under a fed condition. However, it is not clear whether this difference resulted from the food intake or the dose of activated charcoal. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.08.008DOI Listing
February 2019
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Regulated LC-MS/MS bioanalysis technology for therapeutic antibodies and Fc-fusion proteins using structure-indicated approach.

Drug Metab Pharmacokinet 2019 Feb 19;34(1):19-24. Epub 2018 Oct 19.

Leading Technology of Bioanalysis and Protein Chemistry, Shimadzu Corporation, Japan; Shimadzu Bioscience Research Partnership, Shimadzu Scientific Instruments, USA. Electronic address:

In recent studies, the development of bioanalysis technologies using liquid chromatography-tandem mass spectrometry (LC-MS/MS) has attracted attention. Our developed nano-surface and molecular-orientation limited (nSMOL) proteolysis enables Fab-specific proteolysis and is optimal for LC-MS/MS analysis of antibody drugs and Fc-fusion proteins in biological samples. In this nSMOL method, antibodies and Fc-fusion proteins are held in pores of the particle and the subsequent proteolysis is carried out with protease-immobilized nanoparticles. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S13474367183013
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http://dx.doi.org/10.1016/j.dmpk.2018.10.002DOI Listing
February 2019
9 Reads

A spatial-temporal model for zonal hepatotoxicity of acetaminophen.

Drug Metab Pharmacokinet 2019 Feb 8;34(1):71-77. Epub 2018 Oct 8.

Auckland Bioengineering Institute, The University of Auckland, New Zealand. Electronic address:

The metabolism zonation in liver lobules is well known yet its incorporation into the mathematical models of acetaminophen (APAP) metabolism is still primitive - only the oxidation pathway via reaction with the cytochrome P450 (CYP450) has been considered, yet the zonal heterogeneity exhibits in all three pathways including sulphation, glucuronidation and oxidation. In this paper we present a novel computational method where an intracellular APAP metabolism model is integrated into a Finite Element Model (FEM) of sinusoids, and the zonal heterogeneity in three metabolism pathways are all incorporated. We demonstrate that the degradation of APAP, detoxification via glutathione (GSH) and the formation of hepatotoxicity, are all affected profoundly by the zonal difference. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.09.266DOI Listing
February 2019
2 Reads

Functional characterization of 50 CYP2D6 allelic variants by assessing primaquine 5-hydroxylation.

Drug Metab Pharmacokinet 2018 Dec 25;33(6):250-257. Epub 2018 Aug 25.

Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan; Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8575, Japan; Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai 980-8574, Japan; Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, 980-8575, Japan. Electronic address:

Cytochrome P450 2D6 (CYP2D6) is responsible for the metabolic activation of primaquine, an antimalarial drug. CYP2D6 is genetically polymorphic, and these polymorphisms are associated with interindividual variations observed in the therapeutic efficacy of primaquine. To further understand this association, we performed in vitro enzymatic analyses of the wild-type CYP2D6. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.08.004DOI Listing
December 2018
4 Reads

Gap between the US and Japan in coverage of pharmacogenomic biomarkers by health insurance programs: More coverage is needed in Japan.

Drug Metab Pharmacokinet 2018 Dec 1;33(6):243-249. Epub 2018 Sep 1.

Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. Electronic address:

In this study, we aimed to understand the gap in coverage of pharmacogenomic (PGx) biomarkers between Japan and the US. PGx biomarkers (1) in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines; (2) that are CPIC level A or B; or (3) have US Food and Drug Administration (FDA)-approved drug labels, were determined. Subsequently, their coverage by US health insurance companies and the National Health Insurance (NHI) in Japan was investigated. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.08.006DOI Listing
December 2018
1 Read

Characterization of changes in HbA1c in patients with and without secondary failure after metformin treatments by a population pharmacodynamic analysis using mixture models.

Drug Metab Pharmacokinet 2018 Dec 16;33(6):264-269. Epub 2018 Aug 16.

Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan. Electronic address:

The objective of the present study was to develop a population pharmacodynamic (PPD) model to describe the glycated hemoglobin (HbA1c)-lowering effects of metformin in type 2 diabetes mellitus patients with and without secondary failure and to characterize changes in HbA1c levels in the two subpopulations using a mixture model. Information on patients was collected retrospectively from electronic medical records. In this study, the mixture model was used to characterize the bimodal effects of metformin. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S13474367173023
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http://dx.doi.org/10.1016/j.dmpk.2018.08.002DOI Listing
December 2018
10 Reads

Valproic acid transport in the choriocarcinoma placenta cell line JEG-3 proceeds independently of the proton-dependent transporters MCT1 and MCT4.

Drug Metab Pharmacokinet 2018 Dec 5;33(6):270-274. Epub 2018 Apr 5.

Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan; Department of Pharmacy, Hokkaido University Hospital, Sapporo 060-8648, Japan. Electronic address:

Medication therapy is the first line of treatment in the management of epilepsy. Fetal exposure to valproic acid (VPA), an antiepileptic drug, poses an elevated risk of teratogenicity in early pregnancy. Some studies have reported that monocarboxylate transporters (MCTs) may be involved in the placental transport of VPA. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.03.004DOI Listing
December 2018
3 Reads

ABCG2 rs2231142 (Q141K) and oxypurinol concentrations in people with gout receiving allopurinol.

Drug Metab Pharmacokinet 2018 Dec 18;33(6):241-242. Epub 2018 Sep 18.

Department of Medicine, University of Auckland, 85 Park Rd, Grafton, Auckland, 1023, New Zealand.

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https://linkinghub.elsevier.com/retrieve/pii/S13474367183010
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http://dx.doi.org/10.1016/j.dmpk.2018.09.002DOI Listing
December 2018
7 Reads

Development and application of a rapid and sensitive genotyping method for pharmacogene variants using the single-stranded tag hybridization chromatographic printed-array strip (STH-PAS).

Drug Metab Pharmacokinet 2018 Dec 22;33(6):258-263. Epub 2018 Aug 22.

Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba Aramaki, Aoba-ku, Sendai, 980-8578, Japan; Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, 980-8575, Japan; Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan; Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan. Electronic address:

Genetic polymorphisms contribute to inter-individual variability in the metabolism of multiple clinical drugs, including warfarin, thiopurines, primaquine, and aminoglycosides. A rapid and sensitive clinical assessment of various genome biomarkers is, therefore, required to predict the individual responsiveness of each patient to these drugs. In this study, we developed a novel genotyping method for the detection of nine pharmacogene variants that are important in the prediction of drug efficiency and toxicity. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.08.003DOI Listing
December 2018
5 Reads

Uptake and metabolism of mizoribine, an immunosuppressant, in L5178Y-R mouse lymphoma cells in vitro and peripheral blood mononuclear cells of rats and kidney transplant recipients in vivo.

Drug Metab Pharmacokinet 2018 Oct 25;33(5):232-239. Epub 2018 Aug 25.

Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.

The cellular uptake of mizoribine (MZR), an immunosuppressant, and metabolism of MZR to MZR-5'- monophosphate (MZRP), an active metabolite, were evaluated in L5178Y-R mouse lymphoma cells and peripheral blood mononuclear cells (PBMCs) of rats and kidney transplant recipients (KTRs, n = 22). Real-time PCR analysis revealed the expression of ENT1 and ENT2 mRNAs, but not of CNTs, in L5178Y-R cells and rat's PBMCs. In L5178Y-R cells, the uptake of MZR was suppressed by adenosine, a substrate for ENT1 and ENT2, but not by 5-(4-nitrobenzyl)-6-thioinosine (0. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.08.007DOI Listing
October 2018
1 Read
2.570 Impact Factor

Celecoxib is a substrate of CYP2D6: Impact on celecoxib metabolism in individuals with CYP2C9*3 variants.

Drug Metab Pharmacokinet 2018 Oct 19;33(5):219-227. Epub 2018 Jun 19.

Drug Metabolism and Pharmacokinetics Department, Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA. Electronic address:

Celecoxib was characterized as a substrate of human cytochrome P450 (CYP) 2D6 in vitro. In recombinant CYP2D6, celecoxib hydroxylation showed atypical substrate inhibition kinetics with apparent K, K, and V of 67.2 μM, 12. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S13474367183006
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http://dx.doi.org/10.1016/j.dmpk.2018.06.001DOI Listing
October 2018
11 Reads

HLA-B*58:01 and rs9263726 have a linkage, but not absolute linkage disequilibrium in Han Chinese population.

Drug Metab Pharmacokinet 2018 Oct 14;33(5):228-231. Epub 2018 Aug 14.

Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China.

HLA-B*58:01 has been demonstrated to be associated with allopurinol-induced severe cutaneous adverse reactions. Since HLA-B*58:01 is too complicated to be identified, it is necessary to select an appropriate surrogate biomarker. In Japan, the rs9263726 allele was considered as a surrogate biomarker for HLA-B*58:01, but this was not the case with the Australian cohort. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.08.001DOI Listing
October 2018
9 Reads

Genetic variations in the monocarboxylate transporter genes (SLC16A1, SLC16A3, and SLC16A11) in the Japanese population.

Drug Metab Pharmacokinet 2018 Oct 1;33(5):215-218. Epub 2018 Jun 1.

Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-Jo, Nishi-6-chome, Kita-ku, Sapporo, 060-0812, Japan; Department of Pharmacy, Hokkaido University Hospital, Sapporo, 060-8648, Japan. Electronic address:

MCT1 (SLC16A1), MCT4 (SLC16A3), and MCT11 (SLC16A11) are members of the monocarboxylate transporter (MCT) family. MCT1 and MCT4 transport pH-related monocarboxylates, such as lactate and pyruvate. MCT11 may also be a proton-coupled monocarboxylate transporter. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S13474367173020
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http://dx.doi.org/10.1016/j.dmpk.2018.05.001DOI Listing
October 2018
2 Reads

miR-141-3p commonly regulates human UGT1A isoforms via different mechanisms.

Drug Metab Pharmacokinet 2018 Aug 16;33(4):203-210. Epub 2018 May 16.

Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Japan; WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Electronic address:

UDP-Glucuronosyltransferase (UGT) 1A enzymes catalyze the glucuronidation of various compounds. Since no correlation was observed between the protein and mRNA expression of some UGT1A isoforms in the human liver, the involvement of post-transcriptional regulation was hypothesized. We examined whether microRNAs (miRNAs) regulate human UGT1A, focusing on the predicted miR-141-3p. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.05.002DOI Listing
August 2018
10 Reads

Bisphenol A induces Nrf2-dependent drug-metabolizing enzymes through nitrosylation of Keap1.

Drug Metab Pharmacokinet 2018 Aug 22;33(4):194-202. Epub 2018 Apr 22.

Department of Biomedical Chemistry, School of Science and Technology, Kwansei Gakuin University, Japan. Electronic address:

Bisphenol A (BPA) is an endocrine-disrupting chemical, and activates the aryl hydrocarbon receptor (AhR) and the estrogen receptor, leading to the induction of drug metabolizing enzymes. In this study, we found that BPA increased nitric oxide (NO) levels but not reactive oxygen species (ROS) levels in the human hepatoma cell line, Hep3B, and induced drug-metabolizing enzymes such as UDP-glucuronosyltransferase (UGT). Nuclear factor erythroid 2-related factor 2 (Nrf2) has been reported to be activated by ROS through inactivation of its regulating protein, Kelch-like ECH-associated protein (Keap1), and to be the key mediator of phase I and phase II drug metabolizing enzymes, and phase III drug transporters. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.04.003DOI Listing
August 2018
2 Reads

The regulation mechanism of AhR activated by benzo[a]pyrene for CYP expression are different between 2D and 3D culture of human lung cancer cells.

Drug Metab Pharmacokinet 2018 Aug 24;33(4):211-214. Epub 2018 Apr 24.

Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuda, Yahaba-CHO, Siwa-Gun, Iwate 028-3694, Japan.

Most of cytochrome P450 (CYP) expressions are regulated by nuclear receptors. The regulation pathways of transcription are activated by binding of the ligand to the receptor. Many combination of CYPs and nuclear receptors in transcriptional regulation have been reported. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.04.002DOI Listing
August 2018
2 Reads

Derivation of CYP3A4 and CYP2B6 degradation rate constants in primary human hepatocytes: A siRNA-silencing-based approach.

Drug Metab Pharmacokinet 2018 Aug 16;33(4):179-187. Epub 2018 Mar 16.

Department of Molecular and Clinical Pharmacology, The University of Liverpool, 70 Pembroke Place, Liverpool, L69 3GF, UK. Electronic address:

The first-order degradation rate constant (k) of cytochrome P450 (CYP) enzymes is a known source of uncertainty in the prediction of time-dependent drug-drug interactions (DDIs) in physiologically-based pharmacokinetic (PBPK) modelling. This study aimed to measure CYP k using siRNA to suppress CYP expression in primary human hepatocytes followed by incubation over a time-course and tracking of protein expression and activity to observe degradation. The magnitude of gene knockdown was determined by qPCR and activity was measured by probe substrate metabolite formation and CYP2B6-Glo™ assay. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.01.004DOI Listing
August 2018
8 Reads

An analysis on distribution and inter-relationships of biomarkers under rivaroxaban in Japanese patients with non-valvular atrial fibrillation (CVI ARO 1).

Drug Metab Pharmacokinet 2018 Aug 15;33(4):188-193. Epub 2018 Mar 15.

Department of Cardiovascular Medicine, The Cardiovascular Institute, Tokyo, Japan.

Prothrombin time (PT) has been widely used for measuring anticoagulation intensity under rivaroxaban therapy, but precise information has not been well established yet. Consecutive 96 non-valvular atrial fibrillation (NVAF) under rivaroxaban between Jan/June, 2015 were recruited. Serum concentration (SC) and PT with 5 representative reagents available in Japan (Neoplastin Plus®, Thromborel S®, Thrombocheck PT®, Thrombocheck PT Plus®, and Recombiplastin®) at 2-4 hours after (peak) and before intake of rivaroxaban (trough) were measured at outpatient clinic in the cardiovascular institute (CVI ARO study 1). Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.02.002DOI Listing
August 2018
11 Reads

Terfenadone is a strong inhibitor of CYP2J2 present in the human liver and intestinal microsomes.

Drug Metab Pharmacokinet 2018 Jun 15;33(3):159-163. Epub 2018 Mar 15.

BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, South Korea. Electronic address:

Cytochrome P450 2J2 (CYP2J2) is involved in the metabolism of drugs, including albendazole, astemizole, ebastine, and endogenous substrates. In a previous study, we used recombinant CYP2J2 and determined whether danazol, hydroxyebastine, telmisartan, and terfenadone inhibited CYP2J2 by using four representative CYP2J2 substrates, namely albendazole, astemizole, ebastine, and terfenadine. In this study, we evaluated the inhibitory potential of these four chemicals on human liver and intestinal microsomes, which are commonly used in a reaction phenotyping study. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S13474367173011
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http://dx.doi.org/10.1016/j.dmpk.2018.02.001DOI Listing
June 2018
23 Reads

Assessment of induced CYP3A activity in pregnant women using 4β-hydroxycholesterol: Cholesterol ratio as an appropriate metabolic marker.

Drug Metab Pharmacokinet 2018 Jun 25;33(3):173-178. Epub 2018 Apr 25.

Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea. Electronic address:

Aims: This study was aimed at evaluating changes in CYP3A activity following and during pregnancy by analyzing metabolic markers for CYP3A activity, which can help avoid unnecessary drug exposure and invasive sampling.

Methods: Forty-eight pregnant women and 25 non-pregnant women were enrolled in this study. Plasma and urine samples were collected from the pregnant women during each trimester and from the non-pregnant women for evaluation of metabolic markers for CYP3A activity. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.04.004DOI Listing
June 2018
5 Reads

Total hepatocellular disposition profiling of rosuvastatin and pitavastatin in sandwich-cultured human hepatocytes.

Drug Metab Pharmacokinet 2018 Jun 9;33(3):164-172. Epub 2018 Apr 9.

Sugiyama Laboratory, RIKEN Innovation Center, RIKEN, Kanagawa, Japan.

This study describes the total disposition profiling of rosuvastatin (RSV) and pitavastatin (PTV) using a single systematic procedure called D-PREX (Disposition Profile Exploration) in sandwich-cultured human hepatocytes (SCHH). The biliary excretion fractions of both statins were clearly observed, which were significantly decreased dependent on the concentration of Ko143, an inhibitor for breast cancer resistance protein (BCRP). Ko143 also decreased the basolateral efflux fraction of RSV, whereas that of PTV was not significantly affected. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.04.001DOI Listing
June 2018
3 Reads

Points-to-consider documents: Scientific information on the evaluation of genetic polymorphisms during non-clinical studies and phase I clinical trials in the Japanese population.

Drug Metab Pharmacokinet 2018 Jun 15;33(3):141-149. Epub 2018 Mar 15.

Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan; National Institute of Health Sciences (NIHS), Tokyo, Japan.

Pharmacotherapy shows striking individual differences in pharmacokinetics and pharmacodynamics, involving drug efficacy and adverse reactions. Recent genetic research has revealed that genetic polymorphisms are important intrinsic factors for these inter-individual differences. This pharmacogenomic information could help develop safer and more effective precision pharmacotherapies and thus, regulatory guidance/guidelines were developed in this area, especially in the EU and US. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.01.005DOI Listing
June 2018
11 Reads

Importance of cynomolgus monkeys in development of monoclonal antibody drugs.

Drug Metab Pharmacokinet 2019 Feb 20;34(1):55-63. Epub 2018 Mar 20.

Showa Pharmaceutical University, 3-3165 Tamagawagakuen, Machida, Tokyo 194-8543, Japan.

Animal species used in the preclinical studies for development of monoclonal antibody (mAb) drugs are surveyed in this review. Relevant animal species for preclinical studies of mAb candidates are those express desired epitope of mAb candidates. Cynomolgus monkeys cross-react with mAb drugs much higher than other animal species commonly used in preclinical studies such as absorption, distribution, metabolism and excretion (ADME), efficacy, and toxicity studies, for development of new drugs. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.02.003DOI Listing
February 2019
6 Reads

A randomized, placebo-controlled, single ascending-dose study to assess the safety, tolerability, pharmacokinetics, and immunogenicity of subcutaneous tralokinumab in Japanese healthy volunteers.

Drug Metab Pharmacokinet 2018 Jun 12;33(3):150-158. Epub 2017 Dec 12.

California Clinical Trials Medical Group, Inc., Glendale, CA, USA.

Tralokinumab is a human monoclonal antibody in clinical development for asthma and atopic dermatitis that specifically neutralizes interleukin-13. This phase I, single-blind, randomized, placebo-controlled, single ascending-dose study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of subcutaneous tralokinumab (150, 300, or 600 mg) in thirty healthy Japanese adults. The most frequent treatment-emergent adverse event (TEAE) in all treatment groups was injection-site pain. Read More

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http://dx.doi.org/10.1016/j.dmpk.2017.12.001DOI Listing
June 2018
4 Reads

Comparison of protein expression between human livers and the hepatic cell lines HepG2, Hep3B, and Huh7 using SWATH and MRM-HR proteomics: Focusing on drug-metabolizing enzymes.

Drug Metab Pharmacokinet 2018 Apr 10;33(2):133-140. Epub 2018 Mar 10.

Department of Clinical Pharmacy, University of Michigan, Ann Arbor, MI 48109, United States. Electronic address:

Human hepatic cell lines are widely used as an in vitro model for the study of drug metabolism and liver toxicity. However, the validity of this model is still a subject of debate because the expressions of various proteins in the cell lines, including drug-metabolizing enzymes (DMEs), can differ significantly from those in human livers. In the present study, we first conducted an untargeted proteomics analysis of the microsomes of the cell lines HepG2, Hep3B, and Huh7, and compared them to human livers using a sequential window acquisition of all theoretical mass spectra (SWATH) method. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309175PMC
April 2018
10 Reads

Collaborative study using common samples to evaluate the performance of anti-drug antibody assays constructed by different companies.

Drug Metab Pharmacokinet 2018 Apr 8;33(2):125-132. Epub 2018 Mar 8.

Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku Kawasaki-shi, Kanagawa, 210-9501, Japan; Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Japan.

This study was undertaken to evaluate the performance of anti-drug antibody (ADA) assays constructed by each participating company using common samples including ADA, drug and human serum. The ADA assays constructed by each company showed good sensitivity and precision for evaluation of ADA. Cut points for screening and confirmatory assays and assay selectivity were determined by various calculation methods. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S13474367183004
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http://dx.doi.org/10.1016/j.dmpk.2018.03.002DOI Listing
April 2018
14 Reads

A phase I, open-label, single-dose micro tracer mass balance study of C-labeled ASP7991 in healthy Japanese male subjects using accelerator mass spectrometry.

Drug Metab Pharmacokinet 2018 Apr 7;33(2):118-124. Epub 2018 Mar 7.

Research Program Management, Astellas Pharma Inc., 21 Miyukigaoka Tsukuba-shi, Ibaraki, 305-8585, Japan. Electronic address:

ASP7991 is a calcimimetic that acts on the calcium-sensing receptor on parathyroid cell membranes and suppresses parathyroid hormone (PTH) secretion in the treatment of secondary hyperparathyroidism. The mass balance and metabolite profile of [C]ASP7991 were investigated in six healthy male subjects after a single oral dose of [C]ASP7991 [1 mg, 18.5 kBq (500 nCi)] in solution. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S13474367183004
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http://dx.doi.org/10.1016/j.dmpk.2018.03.001DOI Listing
April 2018
13 Reads

Selective inhibition of CYP2C8 by fisetin and its methylated metabolite, geraldol, in human liver microsomes.

Drug Metab Pharmacokinet 2018 Apr 31;33(2):111-117. Epub 2018 Jan 31.

BK21 Plus KNU Multi-Omics-based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea. Electronic address:

Fisetin is a flavonol compound commonly found in edible vegetables and fruits. It has anti-tumor, antioxidant, and anti-inflammatory effects. Geraldol, the O-methyl metabolite of fisetin in mice, is reported to suppress endothelial cell migration and proliferation. Read More

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http://dx.doi.org/10.1016/j.dmpk.2017.12.006DOI Listing
April 2018
9 Reads

A CYP2B6-humanized mouse model and its potential applications.

Drug Metab Pharmacokinet 2018 Feb 11;33(1):2-8. Epub 2018 Jan 11.

Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, USA. Electronic address:

CYP2B6 is a human microsomal cytochrome P450 enzyme with broad substrate selectivity. CYP2B6 is the only functional member of the human CYP2B gene subfamily, which differs from the situation in rodents, such as mouse, where multiple functional Cyp2b genes are expressed. Recent studies with Cyp2b knockout or knockdown mouse models have yielded insights into the in vivo roles of mouse CYP2B enzymes in drug disposition and xenobiotic toxicity. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.01.001DOI Listing
February 2018
14 Reads

Organs-on-a-chip: Current applications and consideration points for in vitro ADME-Tox studies.

Authors:
Seiichi Ishida

Drug Metab Pharmacokinet 2018 Feb 11;33(1):49-54. Epub 2018 Jan 11.

Division of Pharmacology, National Institute of Health Sciences, Japan. Electronic address:

Assay systems using in vitro cultured cells are increasingly applied for evaluation of the efficacy, safety, and toxicity of drug candidates. In vitro cell-based assays have two main applications in the drug discovery process: searching for a compound that is effective against the target disease (seed investigation) and confirmation of safety during use of the identified compounds (safety assessment). Currently available in vitro cell-based assays have been designed to evaluate the efficacy and toxicity in single organs, but the in vivo pharmacokinetics and pharmacodynamics of the administered drug candidates have not been considered. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.01.003DOI Listing
February 2018
17 Reads

Human and mouse artificial chromosome technologies for studies of pharmacokinetics and toxicokinetics.

Drug Metab Pharmacokinet 2018 Feb 11;33(1):17-30. Epub 2018 Jan 11.

Chromosome Engineering Research Center (CERC), Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan; Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan. Electronic address:

In the earliest stage of drug discovery/development, various cell-based models and animal models were used for the prediction of human pharmacokinetics and toxicokinetics. Unfortunately, drugs under development are often discontinued because their nonclinical results do not extrapolate to human clinical studies in relation to either safety or efficacy. Therefore, it is important to improve the time- and cost-effectiveness of drug development. Read More

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http://dx.doi.org/10.1016/j.dmpk.2018.01.002DOI Listing
February 2018
15 Reads

Quantitative analysis of elevation of serum creatinine via renal transporter inhibition by trimethoprim in healthy subjects using physiologically-based pharmacokinetic model.

Drug Metab Pharmacokinet 2018 Feb 5;33(1):103-110. Epub 2017 Dec 5.

Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan. Electronic address:

Serum creatinine (SCr) levels rise during trimethoprim therapy for infectious diseases. This study aimed to investigate whether the elevation of SCr can be quantitatively explained using a physiologically-based pharmacokinetic (PBPK) model incorporating inhibition by trimethoprim on tubular secretion of creatinine via renal transporters such as organic cation transporter 2 (OCT2), OCT3, multidrug and toxin extrusion protein 1 (MATE1), and MATE2-K. Firstly, pharmacokinetic parameters in the PBPK model of trimethoprim were determined to reproduce the blood concentration profile after a single intravenous and oral administration of trimethoprim in healthy subjects. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S13474367173018
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http://dx.doi.org/10.1016/j.dmpk.2017.11.314DOI Listing
February 2018
10 Reads

Investigation of the transport of xanthine dehydrogenase inhibitors by the urate transporter ABCG2.

Drug Metab Pharmacokinet 2018 Feb 22;33(1):77-81. Epub 2017 Nov 22.

Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan. Electronic address:

Hyperuricemia induces gout and kidney stones and accelerates the progression of renal and cardiovascular diseases. Adenosine 5'-triphosphate-binding cassette subfamily G member 2 (ABCG2) is a urate transporter, and common dysfunctional variants of ABCG2, non-functional Q126X (rs72552713) and semi-functional Q141K (rs2231142), are risk factors for hyperuricemia and gout. A recent genome wide association study suggested that allopurinol, a serum uric acid-lowering drug that inhibits xanthine dehydrogenase, is a potent substrate of ABCG2. Read More

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http://dx.doi.org/10.1016/j.dmpk.2017.11.002DOI Listing
February 2018
16 Reads

Functional characterization of 9 CYP2A13 allelic variants by assessment of nicotine C-oxidation and coumarin 7-hydroxylation.

Drug Metab Pharmacokinet 2018 Feb 22;33(1):82-89. Epub 2017 Nov 22.

Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan; Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, 980-8574, Japan; Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8575, Japan. Electronic address:

Cytochrome P450 2A13 (CYP2A13) is responsible for the metabolism of chemical compounds such as nicotine, coumarin, and tobacco-specific nitrosamine. Several of these compounds have been recognized as procarcinogens activated by CYP2A13. We recently showed that CYP2A13*2 contributes to inter-individual variations observed in bladder cancer susceptibility because CYP2A13*2 might cause a decrease in enzymatic activity. Read More

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http://dx.doi.org/10.1016/j.dmpk.2017.11.004DOI Listing
February 2018
2 Reads