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

Abstract

1. 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.

2. 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.

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.

4. 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.

5. 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:

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

Acknowledgements

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.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This study was supported by the JSPS KAKENHI [Grant-in-Aid for Young Scientists (B), Grant Number: 16K18955].