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THE CANINE CYP1A2 DEFICIENCY POLYMORPHISM DRAMATICALLY AFFECTS THE PHARMACOKINETICS OF 4-CYCLOHEXYL-1-ETHYL-7-METHYLPYRIDO[2,3-D]-PYRIMIDINE-2-(1H)-ONE (YM-64227), A PHOSPHODIESTERASE TYPE 4 INHIBITOR

Drug Metabolism Research Laboratories, Astellas Pharma Inc., Tokyo, Japan (D.T., K.N., H.K.); and Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.O., Y.S.)

In a previous study, it was shown that the novel canine single nucleotide polymorphism (SNP) CYP1A2 1117C>T yields an inactive enzyme. In this study, the effect that this SNP has on the pharmacokinetics of 4-cyclohexyl-1-ethyl-7-methylpyrido[2,3-d]pyrimidine-2-(1H)-one (YM-64227) was investigated. Plasma concentrations of the unchanged drug and five of its metabolites (MM-1 to MM-5) were determined after either intravenous or oral administration of YM-64227 to genotyped dogs (C/C, C/T, and T/T groups). Liver microsomes were prepared from these dogs to determine the in vitro metabolic clearance of YM-64227. After a single oral administration, the maximum plasma concentration and absolute bioavailability of YM-64227 in the T/T group were 17.1 times and 27.2 times higher than those in the C/C group, respectively, whereas the pharmacokinetics of YM-64227 after intravenous administration were not affected by genotype. The metabolic profiles in the T/T group were quite distinct from the others; i.e., the main metabolite was MM-2 in the C/C group, whereas MM-1 and MM-5 were the main metabolites in the T/T group. The formation clearances of MM-2 and MM-3 in the microsomes derived from T/T type dogs were significantly lower, whereas those of MM-1, MM-4, and MM-5 were not affected. A statistically significant correlation was observed between the in vivo and in vitro metabolic intrinsic clearances (r = 0.82, p < 0.001). The canine CYP1A2 1117C>T SNP proved to be responsible for a substantial portion of the interindividual variability in the pharmacokinetics of YM-64227.

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				D. Tenmizu, K. Noguchi, and H. Kamimura Elucidation of the Effects of the CYP1A2 Deficiency Polymorphism in the Metabolism of 4-Cyclohexyl-1-ethyl-7-methylpyrido[2,3-d]pyrimidine-2-(1H)-one (YM-64227), a Phosphodiesterase Type 4 Inhibitor, and Its Metabolites in Dogs Drug Metab. Dispos., November 1, 2006; 34(11): 1811 - 1816. [Abstract] [Full Text] [PDF]