Gao Chengcheng1, Xie Rui, Ma Tianheng, Yan Wei, Pang Liqun. 1. Department of Gastroenterology, Huai'an First People's Hospital, Nanjing Medical University, 6 Beijing Road West, Huai'an, Jiangsu 223300, P. R. China.
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 µM and 52.0µM, 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.
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 µM and 52.0µM, 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.
Authors: J Andrew Williams; Barbara J Ring; Varon E Cantrell; Kristina Campanale; David R Jones; Stephen D Hall; Steven A Wrighton Journal: Drug Metab Dispos Date: 2002-11 Impact factor: 3.922
Authors: Chitra Sridar; Theunis C Goosen; Ute M Kent; J Andrew Williams; Paul F Hollenberg Journal: Drug Metab Dispos Date: 2004-06 Impact factor: 3.922
Authors: Brandon T Gufford; Gang Chen; Philip Lazarus; Tyler N Graf; Nicholas H Oberlies; Mary F Paine Journal: Drug Metab Dispos Date: 2014-07-09 Impact factor: 3.922