PT - JOURNAL ARTICLE AU - Shotaro Uehara AU - Nao Yoneda AU - Yuichiro Higuchi AU - Hiroshi Yamazaki AU - Hiroshi Suemizu TI - Human Aldehyde Oxidase 1-mediated Carbazeran Oxidation in Chimeric TK-NOG Mice Transplanted with Human Hepatocytes AID - 10.1124/dmd.120.091090 DP - 2020 Jan 01 TA - Drug Metabolism and Disposition PG - dmd.120.091090 4099 - http://dmd.aspetjournals.org/content/early/2020/04/30/dmd.120.091090.short 4100 - http://dmd.aspetjournals.org/content/early/2020/04/30/dmd.120.091090.full AB - Carbazeran is a potent phosphodiesterase inhibitor with different metabolic profiles in rats, dogs, and humans species-dependently. In this study, we investigated the aldehyde oxidase (AOX)-mediated oxidation of carbazeran to 4-oxo derivatives in chimeric TK-NOG mice with humanized livers (humanized-liver mice). Liver cytosolic fractions from humanized-liver mouse l effectively catalyzed carbazeran 4-oxidation with high affinity for the substrate, similar to those of the human liver cytosolic fractions and recombinant human AOX 1 protein. Furthermore, hepatocytes prepared from humanized-liver mice and humans also exhibited substantial metabolism via carbazeran 4-oxidation. After a single oral administration of carbazeran (10 mg/kg), plasma levels of 4-oxo-carbazeran, N-desethyl-4-oxo-carbazeran, and 6,7-dimethoxy-1-[4-(hydroxy)-piperidino]-4-phthalazinone (three human metabolites formed via 4-oxidation) were higher in humanized-liver mice than in the control mice. In contrast, plasma levels of O-desmethylcarbazeran (a major metabolite in dogs) in control mice were higher than those in the humanized-liver mice. Relative excreted amounts of the three 4-oxidation-derived human specific metabolites in the urine and feces were greater for humanized-liver mice than control mice, whereas the relative excreted amounts of O-desmethylcarbazeran were predominant in the urine and feces of control mice Thus, the production of carbazeran 4-oxo-derivatives was elevated in humanized-liver mice compared with control mice, in agreement with our in vitro enzyme-mediated oxidation data. These results suggest that hepatic human AOX1 functions in humanized-liver mice at the in vivo level and that humanized-liver mice may be useful for predicting drug metabolism in humans, at least with regard to human AOX1-dependent metabolism.SIGNIFICANCE STATEMENT We found that the production of carbazeran 4-oxo-derivatives was higher in humanized-liver mice than in control mice. These results were supported by the fact that carbazeran was rapidly metabolized to 4-oxo-carbazeran in humanized-liver mouse hepatocytes expressing human aldehyde oxidase 1. These results suggest that human aldehyde oxidase 1 is functional in humanized-liver mice in vivo and that chimeric TK-NOG mice transplanted with human hepatocytes may be a suitable model animal for predicting aldehyde oxidase-dependent biotransformation of drugs in humans.