Quantitative prediction of human metabolites formed from the oxidation of the alcohol group of the glucokinase activator, TMG-123, using chimeric mice with humanized livers.

Pharmacokinetic (PK) predictions in humans are important for both the parent compounds and their metabolites, as these predictions help decide whether to progress to human clinical trials. More human PK prediction studies have been conducted on unchanged compounds than on their metabolites. Human PK predictions are more complex for metabolites than for unchanged compounds due to the large number of metabolic enzymes involved and the need to consider species-related differences in these enzymes. Mice with humanized livers are expected to serve as simple and useful tools for assessing a wide range of metabolic enzymes. We confirmed the production of the metabolite formed from the oxidation of the alcohol group of the glucokinase activator, TMG-123, in humans; in addition, we conducted a predictive study on TMG-123 using chimeric mice. Furthermore, we identified the drug-metabolizing enzymes involved in this metabolic reaction. The in vivo production rate of GDI-1202 was 19.1% in humans, 17.0% in chimeric mice, and 5.0% in ICR mice. The main enzyme that metabolizes TMG-123 to GDI-1202 was found to be alcohol dehydrogenase (ADH)/aldehyde dehydrogenase (ALDH). Therefore, chimeric mice are effective animal models for predicting the PK of metabolites formed via the action of non-cytochrome P450 enzymes in humans.