SIGNIFICANCE OF HUMAN IN VITRO STUDIES AND ITS PERSPECTIVE

Abstract

In past years, we experienced some incidents which realize the significance of human in vitro metabolism. In a case of 156-S, this drug caused drug-drug interactions in human clinical study but not observed in rats. Differences between CYP2C enzymes in human and rat were observed in vitro later, and confirmed recently by computational 3D-model analysis. After 156-S and terfenadine incidents, we established human in vitro test system for drug-drug interactions. Rilmazafone was an example that human in vitro studies revealed not to be affected by CYP inhibitors since hydrolysis pathway is the major elimination route. And, in a certain project, in vitro metabolism of compounds with human liver microsomes injected us an insight to chose appropriate lead compound from four candidates. As mentioned above, human in vitro studies give us a lot of important information. As future aspects, human hepatocyte system covers more comprehensive metabolic mechanisms, and useful to postulate metabolites formed in vivo. Further, computational 3D-model analysis of drug metabolizing enzymes will be a powerful tool to estimate metabolic stability and possibility of enzyme inhibition.