Evaluation of interspecies metabolic activities for Non-CYP enzymes, suitable incubation conditions

Evaluation of interspecies metabolic activities for Non-CYP enzymes, suitable incubation conditions

Published:  12/1/2017 1:34:00 PM

Evaluation of interspecies metabolic activities for Non-CYP enzymes and into a suitable incubation condition for human
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).

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