Abstract

1. Corylifol A (CA), a phenolic compound from Psoralea corylifolia, possessed several biological properties but poor bioavailability. Here we aimed to investigate the roles of cytochromes P450s (CYPs), UDP-glucuronosyltransferases (UGTs) and efflux transporters in metabolism and disposition of CA.

2. Metabolism of CA was evaluated in HLM, expressed CYPs and UGTs. Chemical inhibitors and shRNA-mediated gene silencing of multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP) were performed to assess the roles of transporters in CA disposition.

3. Three oxidated metabolites (M1–M3) and two glucuronides (M4–M5) were detected. The intrinsic clearances (CL_int) values of M1 and M4 in HLM were 48.10 and 184.03 μL/min/mg, respectively. Additionally, CYP1A1, 2C8 and 2C19 were identified as main contributors with CL_int values of 13.01–49.36 μL/min/mg, while UGT1A1, 1A7, 1A8 and 1A9 were with CL_int values ranging from 85.01 to 284.07 μL/min/mg. Furthermore, activity correlation analysis proved CYP2C8, UGT1A1 and 1A9 were the main active hepatic isozymes. Besides, rats and monkeys were appropriate model animals. Moreover, dipyridamole and MK571 both could significantly inhibit M4 efflux. Gene silencing results also indicated MRP4 and BCRP were major contributors in HeLa1A1 cells.

4. Taken together, CYPs, UGTs, MRP4 and BCRP were important determinants of CA pharmacokinetics.

摘要

1. Corryifol A（CA）是一种来自补骨脂（Psoralea corylifolia）的酚类化合物，具有几种生物学特性，但生物利用度较差。在这里，我们旨在研究细胞色素P450（CYP），UDP-葡萄糖醛糖基转移酶（UGT）和外排转运蛋白在CA代谢和处置中的作用。

2. 在HLM，表达的CYP和UGT中评估了CA的代谢。进行了多药耐药相关蛋白（MRPs）和乳腺癌耐药蛋白（BCRP）的化学抑制剂和shRNA介导的基因沉默，以评估转运蛋白在CA处置中的作用。

3. 检测到三个氧化代谢物（M1-M3）和两个葡糖醛酸（M4-M5）。HLM中M1和M4的固有清除率（CL _int）值分别为48.10和184.03μL/ min / mg。另外，CYP1A1、2C8和2C19被认为是主要的贡献者，CL _int值为13.01-49.36μL/ min / mg，而UGT1A1、1A7、1A8和1A9的CL _int则为CL _int。值范围从85.01至284.07μL/ min / mg。此外，活性相关分析证明CYP2C8，UGT1A1和1A9是主要的活性肝同工酶。此外，大鼠和猴子是合适的模型动物。此外，双嘧达莫和MK571均可显着抑制M4外排。基因沉默结果还表明，MRP4和BCRP是HeLa1A1细胞的主要贡献者。

4. 两者合计，CYP，UGT，MRP4和BCRP是CA药代动力学的重要决定因素。