Minor contribution of CYP3A5 to the metabolism of hepatitis C protease inhibitor paritaprevir <i>in vitro</i>

<p></p><p>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.</p><p>The aim of this study was to evaluate the effects of cytochrome P450 (CYP) 3A5 on <i>in vitro</i> PTV metabolism using human recombinant CYP3A4, CYP3A5 (rCYP3A4, rCYP3A5) and human liver microsomes (HLMs) genotyped as either <i>CYP3A5*1/*1</i>, <i>CYP3A5*1/*3</i> or <i>CYP3A5*3/*3</i>.</p><p>The intrinsic clearance (CL<sub>int</sub>, <i>V</i><sub>max</sub>/<i>K</i><sub>m</sub>) for the production of a metabolite from PTV in rCYP3A4 was 1.5 times higher than that in rCYP3A5. The PTV metabolism in <i>CYP3A5*1/*1</i> and <i>CYP3A5*1/*3</i> HLMs expressing CYP3A5 was comparable to that in <i>CYP3A5*3/*3</i> HLMs, which lack CYP3A5.</p><p>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.</p><p>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.</p><p></p> <p>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.</p> <p>The aim of this study was to evaluate the effects of cytochrome P450 (CYP) 3A5 on <i>in vitro</i> PTV metabolism using human recombinant CYP3A4, CYP3A5 (rCYP3A4, rCYP3A5) and human liver microsomes (HLMs) genotyped as either <i>CYP3A5*1/*1</i>, <i>CYP3A5*1/*3</i> or <i>CYP3A5*3/*3</i>.</p> <p>The intrinsic clearance (CL<sub>int</sub>, <i>V</i><sub>max</sub>/<i>K</i><sub>m</sub>) for the production of a metabolite from PTV in rCYP3A4 was 1.5 times higher than that in rCYP3A5. The PTV metabolism in <i>CYP3A5*1/*1</i> and <i>CYP3A5*1/*3</i> HLMs expressing CYP3A5 was comparable to that in <i>CYP3A5*3/*3</i> HLMs, which lack CYP3A5.</p> <p>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.</p> <p>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.</p>