Mechanism of dasabuvir inhibition of acetaminophen glucuronidation.

Zhang, Qingchen; Duan, Su Xiang; Harmatz, Jerold S; Wei, Zixuan; Singleton, Christopher A; Greenblatt, David J

Objectives: Acetaminophen (APAP) (paracetamol) is a widely used non-prescription drug for pain relief and antipyretic effects. The clearance of APAP is mainly through phase-2 biotransformation catalysed by UDP-glucuronosyl transferases (UGT). Dasabuvir is an anti-hepatitis C drug reported to inhibit several UGT isoforms. The study evaluated the in-vitro inhibitory capacity of dasabuvir versus APAP glucuronidation. Methods: Procedures included human liver microsomal incubations with APAP and isoform-selective probe substrates. Key findings: Dasabuvir inhibited APAP metabolism by a reversible, mixed-type (competitive and non-competitive) partial inhibition, with an inhibition constant Ki = 3.4 µM. The index constant 'a' was 6.7, indicating the relative contribution of competitive and non-competitive inhibition. The enzyme-inhibitor complex was still able to catalyse the reaction by 12% of the control capacity. Dasabuvir produced strong partial inhibition effect of UGT1A1 and UGT1A9 and relatively complete inhibition of UGT1A6. Conclusions: Consistent with previous reports, dasabuvir inhibits the activity of 3 UGT isoforms associated with APAP metabolism. In-vitro to in-vivo scaling by 2 different approaches showed identical results, predicting an increased AUC of APAP by a factor of 1.3-fold with coadministration of dasabuvir. Until the findings are confirmed in clinical drug interaction studies, APAP dosage should not exceed 3 g per day in dasabuvir-treated patients to avoid potentially hepatotoxic APAP exposures.

ACETAMINOPHEN; GLUCURONIDATION; NONPRESCRIPTION drugs; DRUG interactions; DRUG metabolism; TRANSFERASES; HEPATITIS C

Journal of Pharmacy & Pharmacology, 2022, Vol 74, Issue 1, p131

0022-3573

Academic Journal

10.1093/jpp/rgab144