1. Academic Validation
  2. Effect of CYP3A5*3 genetic variant on the metabolism of direct-acting antivirals in vitro: a different effect on asunaprevir versus daclatasvir and beclabuvir

Effect of CYP3A5*3 genetic variant on the metabolism of direct-acting antivirals in vitro: a different effect on asunaprevir versus daclatasvir and beclabuvir

  • J Hum Genet. 2020 Jan;65(2):143-153. doi: 10.1038/s10038-019-0685-2.
Jun Matsumoto 1 Su Nwe San 2 Masachika Fujiyoshi 3 Ayano Kawauchi 2 Natsumi Chiba 2 Ran Tagai 2 Ryoko Sanbe 2 Shiho Yanaka 2 Hiroaki Sakaue 4 Yoshinori Kato 2 Hiroyoshi Nakamura 2 5 Harumi Yamada 2 Noritaka Ariyoshi 3
Affiliations

Affiliations

  • 1 Department of Personalized Medicine and Preventive Healthcare Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan. matsumotoj@okayama-u.ac.jp.
  • 2 Department of Pharmacokinetics, Pharmaceutical Sciences, International University of Health and Welfare, Tochigi, Japan.
  • 3 Department of Personalized Medicine and Preventive Healthcare Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
  • 4 Department of Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
  • 5 Division of Pharmacy, International University of Health and Welfare Mita Hospital, Tokyo, Japan.
Abstract

Direct-acting antivirals, asunaprevir (ASV), daclatasvir (DCV), and beclabuvir (BCV) are known to be mainly metabolized by CYP3A enzymes; however, the differences in the detailed metabolic activities of CYP3A4 and CYP3A5 on these drugs are not well clarified. The aim of the present study was to elucidate the relative contributions of CYP3A4 and CYP3A5 to the metabolism of ASV, DCV, and BCV, as well as the effect of CYP3A5*3 genetic variant in vitro. The amount of each drug and their major metabolites were determined using LC-MS/MS. Recombinant CYP3As and CYP3A5*3-genotyped human liver microsomes (CYP3A5 expressers or non-expressers) were used for the determination of their metabolic activities. The contribution of CYP3A5 to ASV metabolism was considerable compared to that of CYP3A4. Consistently, ASV metabolic activity in CYP3A5 expressers was higher than those in CYP3A5 non-expresser. Moreover, CYP3A5 expression level was significantly correlated with ASV metabolism. In contrast, these observations were not found in DCV and BCV metabolism. To our knowledge, this is the first study to directly demonstrate the effect of CYP3A5*3 genetic variants on the metabolism of ASV. The findings of the present study may provide basic information on ASV, DCV, and BCV metabolisms.

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