Mechanism of in-vitro inhibition of UGT1A1 by paritaprevir.

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Alam N, Angeli MG, Greenblatt DJ

Mechanism of in-vitro inhibition of UGT1A1 by paritaprevir.

J Pharm Pharmacol. 2017 Dec;69(12):1794-1801. doi: 10.1111/jphp.12821. Epub 2017 Oct 9.

PubMed ID

28990653 [ View in PubMed

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Abstract

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 (Ki ) value for paritaprevir vs EE on average was 20 mum 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. CONCLUSIONS: Paritaprevir 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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Paritaprevir	UDP-glucuronosyltransferase 1-1	Protein	Humans	Unknown	Inhibitor	Details