Journal
JOURNAL OF PHARMACY AND PHARMACOLOGY
Volume 72, Issue 12, Pages 1865-1878Publisher
OXFORD UNIV PRESS
DOI: 10.1111/jphp.13337
Keywords
CYPs; UGTs; drug-drug interactions; isobavachin; metabolism; mice
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Funding
- State Key Laboratory of Drug Research [SIMM1903KF-07]
- Guangdong Basic and Applied Basic Research Foundation [2019A1515011285]
- National Natural Science Foundation of China [81703799, 81803638, 81903704]
- Foundation of He'nan Educational Committee [20A350012]
- Program of Introducing Talents of Discipline to Universities [B13038]
- State Key Program of National Natural Science Foundation of China [81630097]
- Major Project for International Cooperation and Exchange of the National Natural Science Foundation of China [81220108028]
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Objectives Isobavachin is a phenolic with anti-osteoporosis activity. This study aimed to explore its metabolic fatesin vivoandin 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 mu l/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 mu l/min per mg. UGT1As displayed CL(int)values from 10.73 to 202.62 mu l/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 withK(i)values from 0.05 to 3.05 mu m. Conclusions CYP1A2, 2C19 and UGT1As play an important role in isobavachin metabolism. Isobavachin demonstrated broad-spectrum inhibition of CYPs and UGTs.
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