TY - JOUR T1 - THE CANINE CYP1A2 DEFICIENCY POLYMORPHISM DRAMATICALLY AFFECTS THE PHARMACOKINETICS OF 4-CYCLOHEXYL-1-ETHYL-7-METHYLPYRIDO[2,3-<em>D</em>]-PYRIMIDINE-2-(1<em>H</em>)-ONE (YM-64227), A PHOSPHODIESTERASE TYPE 4 INHIBITOR JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 800 LP - 806 DO - 10.1124/dmd.105.008722 VL - 34 IS - 5 AU - Daisuke Tenmizu AU - Kiyoshi Noguchi AU - Hidetaka Kamimura AU - Hisakazu Ohtani AU - Yasufumi Sawada Y1 - 2006/05/01 UR - http://dmd.aspetjournals.org/content/34/5/800.abstract N2 - In a previous study, it was shown that the novel canine single nucleotide polymorphism (SNP) CYP1A2 1117C&gt;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 &lt; 0.001). The canine CYP1A2 1117C&gt;T SNP proved to be responsible for a substantial portion of the interindividual variability in the pharmacokinetics of YM-64227. The American Society for Pharmacology and Experimental Therapeutics ER -