Mechanism of in-vitro inhibition of UGT1A1 by paritaprevir

Objectives: The 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.

Methods: Enzyme 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 findings: The underlying pattern of EE kinetics was complex, with evidence of substrate inhibition. The in-vitro inhibition constant (K_i ) 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 K_i was <0.1.

Conclusions: Paritaprevir is an in-vitro inhibitor of UGT 1A1. However, the in-vitro K_i value relative to maximum clinical plasma concentrations is below the threshold to trigger a recommendation for pharmacokinetic drug interaction studies.