Abstract
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.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.008722.
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ABBREVIATIONS: P450, cytochrome P450; SNP, single nucleotide polymorphism; YM-64227, 4-cyclohexyl-1-ethyl-7-methylpyrido[2,3-d]pyrimidine-2-(1H)-one; HPLC, high-performance liquid chromatography; AUCiv, area under the plasma concentration-time curve after intravenous administration; AUCoral, area under the plasma concentration-time curve after oral administration, CLint,in vitro, overall intrinsic metabolic clearance estimated from the in vitro study; CLint,in vivo, overall intrinsic hepatic clearance calculated based on the in vivo pharmacokinetic information; CLint,ns, intrinsic metabolic clearance for the nonsaturable component; CLint,s, intrinsic metabolic clearance for the saturable component; CLoral, oral clearance (CLtot/Foral); CLtot,blood, CLtot/RB.
- Received November 30, 2005.
- Accepted February 3, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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