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 language | English |
|---|---|
| Journal | Xenobiotica |
| DOIs | |
| Publication status | Accepted/In press - Jan 1 2018 |
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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 journal › Article
}
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 -