AbstractObjectivesThe direct-acting protease inhibitor paritaprevir is a new pharmaco-logic option available for treatment of chronic hepatitis C (HCV). Paritaprevir is reported to inhibit human UGT 1A1, but the mechanism of inhibition and its possible clinical consequences are not established. Our objective was to evaluate the in-vitro metabolic interaction between paritaprevir and the oral contraceptive steroid ethinyl estradiol (EE), a UGT 1A1 substrate.MethodsEnzyme kinetic parameters were determined using human liver microsomes for the biotransformation of EE to its glucuronide metabolites, and the potency and mechanism of inhibition by paritaprevir. Probenecid was used as a reference inhibitor for purposes of assay validation.Key findingsThe underlying pattern of EE kinetics was complex, with evidence of substrate inhibition. The in-vitro inhibition constant (Ki) value for paritaprevir vs EE on average was 20 μm and was consistent with a competitive inhibition mechanism. The ratio of in-vivo maximum plasma concentration of paritaprevir to in-vitro Ki was <0.1.ConclusionsParitaprevir is an in-vitro inhibitor of UGT 1A1. However, the in-vitro Ki value relative to maximum clinical plasma concentrations is below the threshold to trigger a recommendation for pharmacokinetic drug interaction studies.