ID | 57497 |
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Su Nwe San
Graduate School of Pharmaceutical Sciences, International University of Health and Welfare
Matsumoto, Jun
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama University
ORCID
Kaken ID
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Saito, Yumi
Department of Pharmaceutical Sciences, School of Pharmacy , International University of Health and Welfare
Koike, Masako
Department of Pharmaceutical Sciences, School of Pharmacy , International University of Health and Welfare
Sakaue, Hiroaki
Department of Biochemistry, School of Pharmacy , Tokyo University of Pharmacy and Life Sciences
Kato, Yoshinori
Department of Pharmaceutical Sciences, School of Pharmacy , International University of Health and Welfare
Fujiyoshi, Masachika
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama University
Ariyoshi, Noritaka
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama University
Yamada, Harumi
Department of Pharmaceutical Sciences, School of Pharmacy , International University of Health and Welfare
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Abstract | Paritaprevir (PTV) is a non-structural protein 3/4A protease inhibitor developed for the treatment of hepatitis C disease as a fixed dose combination of ombitasvir (OBV) and ritonavir (RTV) with or without dasabuvir. The aim of this study was to evaluate the effects of cytochrome P450 (CYP) 3A5 on in vitro PTV metabolism using human recombinant CYP3A4, CYP3A5 (rCYP3A4, rCYP3A5) and human liver microsomes (HLMs) genotyped as either CYP3A5*1/*1, CYP3A5*1/*3 or CYP3A5*3/*3. The intrinsic clearance (CLint, Vmax/Km) for the production of a metabolite from PTV in rCYP3A4 was 1.5 times higher than that in rCYP3A5. The PTV metabolism in CYP3A5*1/*1 and CYP3A5*1/*3 HLMs expressing CYP3A5 was comparable to that in CYP3A5*3/*3 HLMs, which lack CYP3A5. CYP3A4 expression level was significantly correlated with PTV disappearance rate and metabolite formation. In contrast, there was no such correlation found for CYP3A5 expression level. This study represents that the major CYP isoform involved in PTV metabolism is CYP3A4, with CYP3A5 having a minor role in PTV metabolism. The findings of the present study may provide foundational information on PTV metabolism, and may further support dosing practices in HCV-infected patients prescribed PTV-based therapy.
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Keywords | CYP3As
DAA
HCV
LC-MS/MS
human liver microsomes
metabolism
pharmacogenetics
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Published Date | 2018-11-08
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Publication Title |
Xenobiotica
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Volume | volume49
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Issue | issue8
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Publisher | TAYLOR & FRANCIS
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Start Page | 935
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End Page | 944
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ISSN | 00498254
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NCID | AA00891766
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Content Type |
Journal Article
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language |
English
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OAI-PMH Set |
岡山大学
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File Version | author
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Related Url | isVersionOf https://doi.org/10.1080/00498254.2018.1524947
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Funder Name |
Japan Society for the Promotion of Science
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助成番号 | 16K18955
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