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.
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.
Drug Metabolism Research Laboratories, Astellas Pharma Inc., 1-8, Azusawa 1-Chome, Tokyo 174-8511, Japan. daisuke.tenmizu@jp.astellas.com
Daisuke
D
Tenmizu
Kiyoshi
K
Noguchi
Hidetaka
H
Kamimura
Hisakazu
H
Ohtani
Yasufumi
Y
Sawada
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D001711:Biotransformation; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003510:Cyclohexanes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019388:Cytochrome P-450 CYP1A2 / Q000172:deficiency*; D004285:Dogs; D005838:Genotype; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011485:Protein Binding; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics*
C499820:4-cyclohexyl-1-ethyl-7-methylpyrido(2,3-d)pyrimidin-2-(1H)-one; D003510:Cyclohexanes; D010726:Phosphodiesterase Inhibitors; D011743:Pyrimidines; D019388:Cytochrome P-450 CYP1A2; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4