Development of in vitro screening system for CYP based drug interaction

CYP亚型的鉴定和药物相互作用的预测。利用人肝微粒体和重组人CYP亚型鉴定了参与多种药物代谢的人CYP亚型。CYP1A1、CYP3A4、CYP2D6和CYP2C19分别参与了心得安、双吡喃、米安色林和血清素再摄取抑制剂的代谢。这些结果提示，心得安与吸烟、二耀酰胺与红霉素、米安色林与奎尼丁、血清素再摄取抑制剂与奥美拉唑之间可能存在药物相互作用。体内药物相互作用研究。临床研究表明，红霉素使血浆阿普唑仑浓度显著升高，部分患者与地西泮合用可使血浆佐替平浓度升高。从体外数据定量预测体内药物代谢。利用人和大鼠肝微粒体和重组CYP异构体进行体外研究，可以定量预测奥美拉唑的多态性代谢。对于体内外标度，我们做了一些假设：(1)肝外代谢的贡献可以忽略不计；(2)口服奥美拉唑后完全被吸收；(3)在我们使用的浓度范围内未观察到代谢饱和。这些假设在大鼠体内和体外实验中得到了验证。我们还展示了用原代培养的肝细胞在体外研究中预测苯巴比妥酶诱导的可能性。体内最大诱导率和EC50值可以通过体外研究预测。

Identification of CYP isoforms and prediction of drug interaction. Human CYP isoforms involved in the metabolism of several drugs were identified by using human liver microsomes and recombinant human CYP isoforms. CYP1A1, CYP3A4, CYP2D6 and CYP2C19 were supposed to be involved in the metabolism of propranolol, disopyramide, mianserin and serotonin reuptake inhibitors, respectively. These results suggest the possibility of drug interaction between propranolol and smoking, disopyramide and erythromycin, mianserin and quinidine, and serotonin reuptake inhibitors and omeprazole.In vivo drug interaction studies. Clinical studies indicated that the administration of erythromycin significantly increased the plasme alprazolam concentration, and the plasma zotepine concentration of some patients was in creased by co-administration of diazepam.Quantitative prediction of in vivo drug metabolism from in vitro data. Polymorphic metabolism of omeprazole could be quantitatively predicted from in vitro studies using human and rat hepatic microsomes and recombinant CYP isoforms. Some assumptions were made for in vitro-in vivo scaling : (1) contribution of extra hepatic metabolism was negligible, (2) omeprazole was completely absorbed after oral administration, and (3) saturation of metabolism is not observed in the concentration range we used. These assumptions was validated by in vitro and in vivo studies using rat. We also showed the possibility of the prediction of enzyme induction by phenobarbital from in vitro studies using the primary cultured hepatocytes. Maximum inducibility and EC50 values in vivo could be predicted from the in vitro studies.