title: Prediction of human metabolism of FK3453 by aldehyde oxidase using chimeric mice transplanted with human or rat hepatocytes.
abstract: During drug development, it is important to predict the activities of multiple metabolic enzymes, not only cytochrome P450 (P450) but also non-P450 enzymes, such as conjugative enzymes and aldehyde oxidase (AO). In this study, we focused on prediction of AO-mediated human metabolism and pharmacokinetics (PK) of 6-(2-amino-4-phenylpyrimidine-5-yl)-2-isopropylpyridazin-3(2H)-one (FK3453) (Astellas Pharma Inc.), the development of which was suspended due to extremely low exposure in human, despite good oral bioavailability in rat and dog. We examined species difference in oxidative metabolism of the aminopyrimidine moiety of FK3453, catalyzed by AO, using human-chimeric mice with humanized liver (h-PXB mice) and rat-chimeric mice (r-PXB mice) transplanted with rat hepatocytes. AO activity of h-PXB mouse hepatocytes was higher than that of r-PXB mouse hepatocytes. Moreover, higher concentrations of human-specific AO-generated FK3453 metabolite A-M were detected in urine and feces after administration of FK3453 to h-PXB mice versus r-PXB mice. The total clearance of h-PXB mice was 2-fold higher than that of r-PXB mice. These results agreed reasonably well with the metabolism and PK profiles of FK3453 in human and rat. Our results indicated that h-PXB mice should be helpful for predicting the metabolic profile of drugs in humans, and the use of both h-PXB and r-PXB mice should be helpful for evaluation of species differences of AO metabolic activity.
authors: Graduate School of Biomedical Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553 Japan. sanoh@hiroshima-u.ac.jp
authors: Seigo
authors: S
authors: Sanoh
authors: Kazuyoshi
authors: K
authors: Nozaki
authors: Hidetsugu
authors: H
authors: Murai
authors: Shigeyuki
authors: S
authors: Terashita
authors: Toshio
authors: T
authors: Teramura
authors: Shigeru
authors: S
authors: Ohta
mesh_terms: D042931:Aldehyde Oxidase / Q000378:metabolism*; D000818:Animals; D002675:Child, Preschool; D022781:Hepatocytes / Q000378:metabolism* / Q000637:transplantation*; D006801:Humans; D008297:Male; D051379:Mice; D011237:Predictive Value of Tests; D011485:Protein Binding / Q000235:genetics; D011724:Pyridazines / Q000378:metabolism*; D011743:Pyrimidines / Q000378:metabolism*; D011828:Radiation Chimera; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: C561949:FK3453; D011724:Pyridazines; D011743:Pyrimidines; D042931:Aldehyde Oxidase