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ID 57497
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Author
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 researchmap
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
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.
Keywords
CYP3As
DAA
HCV
LC-MS/MS
human liver microsomes
metabolism
pharmacogenetics
Published Date
2018-11-08
Publication Title
Xenobiotica
Volume
volume49
Issue
issue8
Publisher
TAYLOR & FRANCIS
Start Page
935
End Page
944
ISSN
00498254
NCID
AA00891766
Content Type
Journal Article
language
英語
OAI-PMH Set
岡山大学
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author
PubMed ID
DOI
Web of Science KeyUT
Related Url
isVersionOf https://doi.org/10.1080/00498254.2018.1524947
Funder Name
Japan Society for the Promotion of Science
助成番号
16K18955