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 journalArticle

1 Citation (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 (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.

Original languageEnglish
JournalXenobiotica
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Cytochrome P-450 CYP3A
Hepatitis C
Protease Inhibitors
Metabolism
Liver Microsomes
Liver
ABT-450
In Vitro Techniques
Metabolites
Ritonavir

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Toxicology
  • Pharmacology
  • Health, Toxicology and Mutagenesis

Cite this

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, 01.01.2018.

Research output: Contribution to journalArticle

@article{e85a13367b5347f2ac565c3e9566b19f,
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.",
keywords = "CYP3A5*3, CYP3As, DAA, HCV, human liver microsomes, LC-MS/MS, metabolism, pharmacogenetics",
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",
year = "2018",
month = "1",
day = "1",
doi = "10.1080/00498254.2018.1524947",
language = "English",
journal = "Xenobiotica",
issn = "0049-8254",
publisher = "Informa Healthcare",

}

TY - JOUR

T1 - Minor contribution of CYP3A5 to the metabolism of hepatitis C protease inhibitor paritaprevir in vitro

AU - San, Su Nwe

AU - Matsumoto, Jun

AU - Saito, Yumi

AU - Koike, Masako

AU - Sakaue, Hiroaki

AU - Kato, Yoshinori

AU - Fujiyoshi, Masachika

AU - Ariyoshi, Noritaka

AU - Yamada, Harumi

PY - 2018/1/1

Y1 - 2018/1/1

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.

KW - CYP3A53

KW - CYP3As

KW - DAA

KW - HCV

KW - human liver microsomes

KW - LC-MS/MS

KW - metabolism

KW - pharmacogenetics

UR - http://www.scopus.com/inward/record.url?scp=85056167212&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056167212&partnerID=8YFLogxK

U2 - 10.1080/00498254.2018.1524947

DO - 10.1080/00498254.2018.1524947

M3 - Article

C2 - 30227770

AN - SCOPUS:85056167212

JO - Xenobiotica

JF - Xenobiotica

SN - 0049-8254

ER -