Development of in vitro screening system for CYP based drug interaction

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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.