Zhu Lijun, Liu Xiawen, Zhu Liu, Zhang Xingfei, Fu Xiaojing, Huang Junjun, Yuan Mu
The Drug Research Center, Guangzhou Medical University, Guangzhou, China.
J Pharm Pharmacol. 2014 Nov;66(11):1534-51. doi: 10.1111/jphp.12281. Epub 2014 Jun 19.
Naftopidil (NAF) is a chiral compound with two enantiomers (R(+)-NAF and S(-)-NAF) and is used as a racemic mixture in clinical practice. This study aims to investigate the metabolism of NAF enantiomers in pooled human liver microsomes (HLMs) and cytochrome P450 isozymes (CYPs) involved in their metabolism.
Metabolism studies were conducted in vitro using HLMs. Specific chemical inhibitors and recombinant human CYPs were used to confirm that the CYPs contributed to the metabolism of NAF enantiomers.
Three metabolites were found and characterized in the HLMs incubations from R(+)-NAF and S(-)-NAF, respectively. The major metabolic pathways of R(+)-NAF and S(-)-NAF were demethylation and hydroxylation. CYP2C9 and CYP2C19 inhibitors strongly inhibited R(+)-NAF metabolism, and CYP1A2, CYP2C8, CYP2D6 and CYP3A4/5 inhibitors moderately inhibited R(+)-NAF metabolism. CYP2C9 inhibitors strongly inhibited S(-)-NAF metabolism, and CYP2C8, CYP2C19 and CYP3A4/5 inhibitors moderately inhibited S(-)-NAF metabolism. Consistent with the results of chemical inhibitors experiments, recombinant human CYP2C9 and CYP2C19 contributed greatly to R(+)-NAF metabolism, and CYP2C9 contributed greatly to S(-)-NAF metabolism.
Both R(+)-NAF and S(-)-NAF are metabolized to three metabolites in HLMs. CYP2C9 plays the most important role in the demethylation and hydroxylation of both NAF enantiomers, CYP2C19 is another major CYP isoform that is involved in R(+)-NAF metabolism.
萘哌地尔（NAF）是一种具有两种对映体（R(+)-NAF和S(-)-NAF）的手性化合物，在临床实践中以消旋混合物形式使用。本研究旨在调查NAF对映体在人肝微粒体（HLM）中的代谢情况以及参与其代谢的细胞色素P450同工酶（CYP）。
使用HLM进行体外代谢研究。使用特异性化学抑制剂和重组人CYP来确认CYP对NAF对映体代谢的贡献。
分别在R(+)-NAF和S(-)-NAF的HLM孵育中发现并鉴定出三种代谢物。R(+)-NAF和S(-)-NAF的主要代谢途径是去甲基化和羟基化。CYP2C9和CYP2C19抑制剂强烈抑制R(+)-NAF代谢，CYP1A2、CYP2C8、CYP2D6和CYP3A4/5抑制剂中度抑制R(+)-NAF代谢。CYP2C9抑制剂强烈抑制S(-)-NAF代谢，CYP2C8、CYP2C19和CYP3A4/5抑制剂中度抑制S(-)-NAF代谢。与化学抑制剂实验结果一致，重组人CYP2C9和CYP2C19对R(+)-NAF代谢贡献很大，CYP2C9对S(-)-NAF代谢贡献很大。
R(+)-NAF和S(-)-NAF在HLM中均代谢为三种代谢物。CYP2C9在两种NAF对映体的去甲基化和羟基化中起最重要作用，CYP2C19是参与R(+)-NAF代谢的另一种主要CYP同工酶。
