Minor contribution of CYP3A5 to the metabolism of hepatitis C protease inhibitor paritaprevir in vitro

Su Nwe San; Jun Matsumoto; Yumi Saito; Masako Koike; Hiroaki Sakaue; Yoshinori Kato; Masachika Fujiyoshi; Noritaka Ariyoshi; Harumi Yamada

doi:10.1080/00498254.2018.1524947

Minor contribution of CYP3A5 to the metabolism of hepatitis C protease inhibitor paritaprevir in vitro

Su Nwe San, Jun Matsumoto, Yumi Saito, Masako Koike, Hiroaki Sakaue, Yoshinori Kato, Masachika Fujiyoshi, Noritaka Ariyoshi, Harumi Yamada

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

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 (CL_int, V_max/K_m) 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.

Original language	English
Pages (from-to)	935-944
Number of pages	10
Journal	Xenobiotica
Volume	49
Issue number	8
DOIs	https://doi.org/10.1080/00498254.2018.1524947
Publication status	Published - Aug 3 2019

Keywords

CYP3A5*3
CYP3As
DAA
HCV
LC-MS/MS
human liver microsomes
metabolism
pharmacogenetics

ASJC Scopus subject areas

Biochemistry
Toxicology
Pharmacology
Health, Toxicology and Mutagenesis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1080/00498254.2018.1524947

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Minor contribution of CYP3A5 to the metabolism of hepatitis C protease inhibitor paritaprevir in vitro. / San, Su Nwe; Matsumoto, Jun; Saito, Yumi; Koike, Masako; Sakaue, Hiroaki; Kato, Yoshinori; Fujiyoshi, Masachika ; Ariyoshi, Noritaka; Yamada, Harumi.

In: Xenobiotica, Vol. 49, No. 8, 03.08.2019, p. 935-944.

Research output: Contribution to journal › Article › peer-review

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title = "Minor contribution of CYP3A5 to the metabolism of hepatitis C protease inhibitor paritaprevir in vitro",

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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author = "San, {Su Nwe} and Jun Matsumoto and Yumi Saito and Masako Koike and Hiroaki Sakaue and Yoshinori Kato and Masachika Fujiyoshi and Noritaka Ariyoshi and Harumi Yamada",

note = "Funding Information: This study was supported by the JSPS KAKENHI [Grant-in-Aid for Young Scientists (B), Grant Number: 16K18955]. Funding Information: This study was supported by the JSPS KAKENHI [Grant-in-Aid for Young Scientists (B), Grant Number: 16K18955]. We acknowledge Drs. Yasuyuki Momose (International University of Health and Welfare, IUHW), Kayoko Maezawa (IUHW), Takeshi Ito (IUHW) and Natsuko Sugiyama (IUHW) for providing useful suggestions. Publisher Copyright: {\textcopyright} 2018, {\textcopyright} 2018 Informa UK Limited, trading as Taylor & Francis Group.",

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AU - San, Su Nwe

AU - Matsumoto, Jun

AU - Saito, Yumi

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AU - Sakaue, Hiroaki

AU - Kato, Yoshinori

AU - Fujiyoshi, Masachika

AU - Ariyoshi, Noritaka

AU - Yamada, Harumi

N1 - Funding Information: This study was supported by the JSPS KAKENHI [Grant-in-Aid for Young Scientists (B), Grant Number: 16K18955]. Funding Information: This study was supported by the JSPS KAKENHI [Grant-in-Aid for Young Scientists (B), Grant Number: 16K18955]. We acknowledge Drs. Yasuyuki Momose (International University of Health and Welfare, IUHW), Kayoko Maezawa (IUHW), Takeshi Ito (IUHW) and Natsuko Sugiyama (IUHW) for providing useful suggestions. Publisher Copyright: © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.

PY - 2019/8/3

Y1 - 2019/8/3

N2 - 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.

AB - 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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KW - pharmacogenetics

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Minor contribution of CYP3A5 to the metabolism of hepatitis C protease inhibitor paritaprevir in vitro

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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