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

Jun Matsumoto, Su Nwe San, Masachika Fujiyoshi, Ayano Kawauchi, Natsumi Chiba, Ran Tagai, Ryoko Sanbe, Shiho Yanaka, Hiroaki Sakaue, Yoshinori Kato, Hiroyoshi Nakamura, Harumi Yamada, Noritaka Ariyoshi

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalJournal of Human Genetics
DOIs
Publication statusAccepted/In press - Jan 1 2019

Fingerprint

Cytochrome P-450 CYP3A
Antiviral Agents
8-cyclohexyl-N-((dimethylamino)sulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-((3-methyl-3,8-diazabicyclo(3.2.1)oct-8-yl)carbonyl)cycloprop(d)indolo(2,1-a)(2)benzazepine-5-carboxamide
In Vitro Techniques
BMS-790052
asunaprevir
Liver Microsomes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Effect of CYP3A5*3 genetic variant on the metabolism of direct-acting antivirals in vitro : a different effect on asunaprevir versus daclatasvir and beclabuvir. / Matsumoto, Jun; San, Su Nwe; Fujiyoshi, Masachika; Kawauchi, Ayano; Chiba, Natsumi; Tagai, Ran; Sanbe, Ryoko; Yanaka, Shiho; Sakaue, Hiroaki; Kato, Yoshinori; Nakamura, Hiroyoshi; Yamada, Harumi; Ariyoshi, Noritaka.

In: Journal of Human Genetics, 01.01.2019.

Research output: Contribution to journalArticle

Matsumoto, Jun ; San, Su Nwe ; Fujiyoshi, Masachika ; Kawauchi, Ayano ; Chiba, Natsumi ; Tagai, Ran ; Sanbe, Ryoko ; Yanaka, Shiho ; Sakaue, Hiroaki ; Kato, Yoshinori ; Nakamura, Hiroyoshi ; Yamada, Harumi ; Ariyoshi, Noritaka. / Effect of CYP3A5*3 genetic variant on the metabolism of direct-acting antivirals in vitro : a different effect on asunaprevir versus daclatasvir and beclabuvir. In: Journal of Human Genetics. 2019.
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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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T2 - a different effect on asunaprevir versus daclatasvir and beclabuvir

AU - Matsumoto, Jun

AU - San, Su Nwe

AU - Fujiyoshi, Masachika

AU - Kawauchi, Ayano

AU - Chiba, Natsumi

AU - Tagai, Ran

AU - Sanbe, Ryoko

AU - Yanaka, Shiho

AU - Sakaue, Hiroaki

AU - Kato, Yoshinori

AU - Nakamura, Hiroyoshi

AU - Yamada, Harumi

AU - Ariyoshi, Noritaka

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AB - 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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