Open AccessInvestigation on the metabolic characteristics of isobavachin in Psoralea corylifolia L. (Bu‐gu‐zhi) and its potential inhibition against human cytochrome P450s and UDP‐glucuronosyltransferases
Author(s) -
Xing Han,
Yang Jing,
Ren Kaidi,
Qin Zifei,
Wang Peile,
Zhang Xiaojian,
Yao Zhihong,
Gonzalez Frank J.,
Yao Xinsheng
Publication year - 2020
Publication title -
journal of pharmacy and pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.745
H-Index - 118
eISSN - 2042-7158
pISSN - 0022-3573
DOI - 10.1111/jphp.13337
Subject(s) - glucuronidation , cyp1a2 , microsome , chemistry , pharmacology , metabolism , psoralea corylifolia , drug metabolism , cytochrome p450 , glucuronosyltransferase , biochemistry , enzyme , biology , medicine , alternative medicine , pathology
Objectives Isobavachin is a phenolic with anti‐osteoporosis activity. This study aimed to explore its metabolic fates in vivo and in vitro , and to investigate the potential drug–drug interactions involving CYPs and UGTs. Methods Metabolites of isobavachin in mice were first identified and characterized. Oxidation and glucuronidation study were performed using liver and intestine microsomes. Reaction phenotyping, activity correlation analysis and relative activity factor approaches were employed to identify the main CYPs and UGTs involved in isobavachin metabolism. Through kinetic modelling, inhibition mechanisms towards CYPs and UGTs were also explored. Key findings Two glucuronides (G1 ‐ G2) and three oxidated metabolites (M1 ‐ M3) were identified in mice. Additionally, isobavachin underwent efficient oxidation and glucuronidation by human liver microsomes and HIM with CL int values from 5.53 to 148.79 μl/min per mg. CYP1A2, 2C19 contributed 11.3% and 17.1% to hepatic metabolism of isobavachin, respectively, with CL int values from 8.75 to 77.33 μl/min per mg. UGT1As displayed CL int values from 10.73 to 202.62 μl/min per mg for glucuronidation. Besides, significant correlation analysis also proved that CYP1A2, 2C19 and UGT1A1, 1A9 were main contributors for the metabolism of isobavachin. Furthermore, mice may be the appropriate animal model for predicting its metabolism in human. Moreover, isobavachin exhibited broad inhibition against CYP2B6, 2C9, 2C19, UGT1A1, 1A9, 2B7 with K i values from 0.05 to 3.05 μ m . Conclusions CYP1A2, 2C19 and UGT1As play an important role in isobavachin metabolism. Isobavachin demonstrated broad‐spectrum inhibition of CYPs and UGTs.