Yu Xu1, Peizhong Li1, Xin Zhang1, Junying Wang1, Dongsheng Gu1, Yao Wang2. 1. Department of Otorhinolaryngology, Huai'an First People's Hospital, Nanjing Medical University, 6 Beijing Road West, Huai'an, Jiangsu 223300, P. R. China. 2. Pharmaceutical Preparation Section, Huai'an First People's Hospital, Nanjing Medical University, 6 Beijing Road West, Huai'an, Jiangsu 223300, P. R. China.
Abstract
BACKGROUND: Inhibition of drug-metabolizing enzymes (DMEs) has been regarded as one of the most important reason for clinical drug-drug interaction. AIM: The aim of the present study is to evaluate the inhibition of bakuchiol towards UDP-glucuronosyltransferase (UGT) 2B isoforms. METHODS: In vitro recombinant UGT2B-catalyzed 4-methylumbelliferone glucuronidation was used as the probe reaction. Dixon plot and Lineweaver-Burk plot were employed to determine the inhibition kinetic type, and nonlinear regression of data was utilized to calculate the inhibition kinetic parameter (Ki). In vitro-in vivo extrapolation (IVIVE) was carried out to predict in vivo inhibition magnitude. RESULTS: Among the tested UGT2B isoforms, UGT2B7 was inhibited by the strongest intensity. The noncompetitive inhibition was demonstrated by the results obtained from Dixon plot and Lineweaver-Burk plot. The Ki value was calculated to be 10.7 µM. In combination with the reported concentration after an intravenous administration of bakuchiol (15 mg/kg) in rats, the high risk of in vivo inhibition of bakuchiol towards UGT2B7-catalyzed metabolism of drugs was indicated. CONCLUSION: All these results provide an important information for the risk evaluation of the clinical utilization of bakuchiol.
BACKGROUND: Inhibition of drug-metabolizing enzymes (DMEs) has been regarded as one of the most important reason for clinical drug-drug interaction. AIM: The aim of the present study is to evaluate the inhibition of bakuchiol towards UDP-glucuronosyltransferase (UGT) 2B isoforms. METHODS: In vitro recombinant UGT2B-catalyzed 4-methylumbelliferone glucuronidation was used as the probe reaction. Dixon plot and Lineweaver-Burk plot were employed to determine the inhibition kinetic type, and nonlinear regression of data was utilized to calculate the inhibition kinetic parameter (Ki). In vitro-in vivo extrapolation (IVIVE) was carried out to predict in vivo inhibition magnitude. RESULTS: Among the tested UGT2B isoforms, UGT2B7 was inhibited by the strongest intensity. The noncompetitive inhibition was demonstrated by the results obtained from Dixon plot and Lineweaver-Burk plot. The Ki value was calculated to be 10.7 µM. In combination with the reported concentration after an intravenous administration of bakuchiol (15 mg/kg) in rats, the high risk of in vivo inhibition of bakuchiol towards UGT2B7-catalyzed metabolism of drugs was indicated. CONCLUSION: All these results provide an important information for the risk evaluation of the clinical utilization of bakuchiol.
Authors: Cody J Peer; Tristan M Sissung; Aerang Kim; Lokesh Jain; Sukyung Woo; Erin R Gardner; C Tyler Kirkland; Sarah M Troutman; Bevin C English; Emily D Richardson; Joel Federspiel; David Venzon; William Dahut; Elise Kohn; Shivaani Kummar; Robert Yarchoan; Giuseppe Giaccone; Brigitte Widemann; William D Figg Journal: Clin Cancer Res Date: 2012-02-03 Impact factor: 12.531