Evaluation of interspecies metabolic activities for non-CYP enzymes
Presented at the 32nd Annual Meeting of Japanese Society for the Study of Xenobiotics (JSSX) in Tokyo, Japan
“Evaluation of interspecies metabolic activities for non-CYP enzymes and into a suitable incubation condition for human”
Sho Nishinoaki, Toshimasa Ito, Ryo Fujino, Kenta Hashizume, Shinsuke Aoyama, Shinichi Ninomiya
Drug Development Solutions Center, Drug Development Solutions Division, Sekisui Medical Co., Ltd. 2117 Muramatsu, Tokai, Ibaraki 319-1182, Japan
Recently, lead compound screenings has become widely used in drug development. This has led to the development of increasing range of lead compound structures with metabolic stability for Cytochrome P450 (CYP). However, because of the unpredictable metabolic reaction and species differences by non-CYP enzymes, there have been cases that the test compound’s blood concentration was found to be significantly lower than expected in the clinical phase, resulting in the discontinuation in its development. Therefore, it is necessary to establish an in vitro evaluation system of metabolic activities for non-CYP enzymes.
We evaluated interspecies differences in metabolic activities for non-CYP enzymes (aldehyde oxidase (AO), aldo-keto reductase (AKR) and carbonyl reductase (CR)) in liver cytosol (human, monkey, rat, mouse and dog). We also evaluated the inhibitory effect of typical inhibitor for each non-CYP enzyme (AO, xanthine oxidase (XO), AKR and CR). And, we tested the metabolic activities of non-CYP enzymes in anaerobic conditions using human liver hepatocytes. In this presentation, we have established an evaluation method for metabolic activities of non-CYP enzymes (AO, XO, AKR, CR).