Potential metabolism determinants and drug–drug interactions of a natural flavanone bavachinin

Abstract

Bavachinin, a natural bioactive flavanone, is reported to have many pharmacological proprieties, especially anti-osteoporosis activity. Here we aim to determine the roles of cytochrome P450s (CYP), UDP-glucuronosyltransferases (UGT), and efflux transporters in metabolism and drug–drug interactions (DDI) of bavachinin. Phase I metabolism and glucuronidation were performed by human liver microsomes (HLM) and human intestine microsomes (HIM). Reaction phenotyping was used to identify the main CYPs and UGTs. Gene silencing methods were employed to investigate the roles of breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs) in HeLa1A1 cells. Inhibition mechanisms towards CYPs and UGTs were explored through kinetic modeling. Three phase I metabolites (M1–M3) and one glucuronide (G1) were detected after incubation of bavachinin with HLM and HIM. The intrinsic clearance (CL_int) values of M1 and G1 by HLM were 89.4 and 270.2 μL min⁻¹ mg⁻¹, respectively, while those of M3 and G1 by HIM were 25.8 and 247.1 μL min⁻¹ mg⁻¹, respectively. CYP1A1, 1A2, 1B1, 2C8, 2C19, and UGT1A1, 1A8 participated more in bavachinin metabolism. The metabolism showed marked species difference. BCRP and MRP4 were identified as the main contributors. Bavachinin displayed potent inhibitory effects against several CYP and UGT isozymes (K_i = 0.28–2.53 μM). Bavachinin was subjected to undergo metabolism and disposition by CYPs, UGTs, BCRP, MRP4, and was also a potent non-selective inhibitor against several CYPs and UGTs.