Abstract
Drug-metabolizing enzymes (DMEs) inhibition based drug-drug interaction and herb-drug interaction severely challenge the R&D process of drugs or herbal ingredients. 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. 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. 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 µM and 52.0µM, respectively. 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.
Highlights
Since the beginning of the herbs’ utilization from ancient times, the utilization of herbal medicines has a history of about 4000 years[1]
The present study aims to study the inhibition of wogonin towards one of the most important UGT isoforms, UGT1A9
The inhibition of wogonin towards recombinant UGT1A9-catalyzed 4-MU glucuronidation reaction was evaluated, and the results were shown in figure 1
Summary
Since the beginning of the herbs’ utilization from ancient times, the utilization of herbal medicines has a history of about 4000 years[1]. Herbal components can change the activity of all these DMEs through the good interaction with them. When these herbs are co-administered with the drugs mainly undergoing the DMEs inhibited by herbal components, the exposed concentration of drugs might exceed the African Health Sciences Vol 13 Issue 3 September 2013 minimal toxicity dose in the therapeutic window, and induce severe toxicity. Drug-metabolizing enzymes (DMEs) inhibition based drug-drug interaction and herb-drug interaction severely challenge the R&D process of drugs or herbal ingredients. Results: Wogonin noncompetitively inhibited recombinant UGT1A9-catalyzed 4-MU glucuronidation, and exerted competitive inhibition towards HLMs-catalyzed propofol glucuronidation.
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