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Potential metabolism determinants and drug–drug interactions of a natural flavanone bavachinin
RSC Advances ( IF 3.9 ) Pub Date : 2020-9-23 , DOI: 10.1039/d0ra06961b
Xinqiang Li 1 , Han Xing 2 , Zifei Qin 2 , Jing Yang 2 , Peile Wang 2 , Xiaojian Zhang 2 , Zhihong Yao 3, 4 , Xinsheng Yao 3, 4
Affiliation  

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 (CLint) 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 (Ki = 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.

中文翻译:


天然黄烷酮补二氢黄酮的潜在代谢决定因素和药物相互作用



Bavachinin 是一种天然生物活性黄烷酮,据报道具有许多药理特性,特别是抗骨质疏松活性。在这里,我们的目标是确定细胞色素 P450 (CYP)、UDP-葡萄糖醛酸基转移酶 (UGT) 和外排转运蛋白在补骨脂二氢黄酮代谢和药物相互作用 (DDI) 中的作用。 I 期代谢和葡萄糖醛酸化由人肝微粒体 (HLM) 和人肠微粒体 (HIM) 进行。反应表型用于鉴定主要的 CYP 和 UGT。采用基因沉默方法研究乳腺癌耐药蛋白(BCRP)和多药耐药相关蛋白(MRP)在HeLa1A1细胞中的作用。通过动力学模型探讨了 CYP 和 UGT 的抑制机制。将补骨脂二氢黄酮与 HLM 和 HIM 一起孵育后,检测到三个 I 相代谢物 ( M1–M3 ) 和一种葡萄糖醛酸苷 ( G1 )。 HLM 测定的M1G1的内在清除率 (CL int ) 值分别为 89.4 和 270.2 μL min -1 mg -1 ,而 HIM 测定的M3G1的内在清除率 (CL int ) 值分别为 25.8 和 247.1 μL min -1 mg -1 。 CYP1A1、1A2、1B1、2C8、2C19和UGT1A1、1A8更多地参与补骨脂二氢黄酮代谢。代谢表现出明显的物种差异。 BCRP 和 MRP4 被确定为主要贡献者。 Bavachinin 对多种 CYP 和 UGT 同工酶表现出有效的抑制作用 ( K = 0.28–2.53 μM)。 Bavachinin 受到 CYP、UGT、BCRP、MRP4 的代谢和处置,也是多种 CYP 和 UGT 的有效非选择性抑制剂。
更新日期:2020-09-23
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