Probe substrate and enzyme source-dependent inhibition of UDP-glucuronosyltransferase (UGT) 1A9 by wogonin

C Gao, R Xie, T Ma, W Yan, L Pang

Abstract

Background: Drug-metabolizing enzymes (DMEs) inhibition based drug-drug interaction and herb-drug interaction severely challenge the R&D process of drugs or herbal ingredients.

Objective: To evaluate the inhibition potential of wogonin (an important flavonoid isolated from the root of Scutellaria baicalensis) towards one of the most important phase II DMEs, UDP-glucuronosyltransferase (UGT) 1A9.

Methods: Both recombinant UGT1A9-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction and human liver microsomes (HLMs)-catalyzed propofol glucuronidation reaction were used as two different probe reactions.

Results: Wogonin noncompetitively inhibited recombinant UGT1A9-catalyzed 4-MU glucuronidation, and exerted competitive inhibition towards HLMs-catalyzed propofol glucuronidation. The inhibition kinetic parameters (Ki) were calculated to be 3.2 ìM and 52.0ìM, respectively.

Conclusion: Necessary monitoring was needed when wogonin was co-administered with the clinical drugs mainly undergoing UGT1A9-mediated glucuronidation elimination. Additionally, probe reactions-dependent inhibition of wogonin towards the activity of UGT1A9 should be paid attention when translating these in vitro data into in vivo situation.

Keywords: wogonin, drug-drug interaction (DDI),  UDP-glucuronosyltransferases (UGTs)