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.
The canine CYP1A2 1117 C>T single nucleotide polymorphism is responsible for a substantial portion of the interindividual variability seen in the pharmacokinetics of 4-cyclohexyl-1-ethyl-7-methylpyrido[2,3-d]pyrimidine-2-(1H)-one (YM-64227). The purpose of this study is to investigate the contribution of CYP1A2 to the metabolism of YM-64227 and its five metabolites (MM-1 to MM-5), as well as to determine the interindividual variability between the pharmacokinetic profiles of the compounds with respect to the CYP1A2 deficiency polymorphism. alpha-Naphthoflavone and anti-CYP1A1/2 antibody inhibited the metabolic activities at which MM-2 and MM-3 were formed from YM-64227 in C/C- and C/T-type microsomes. In T/T type, the rate of MM-2 and MM-3 formation was lower, and alpha-naphthoflavone and anti-CYP1A1/2 antibody were shown to have no effect. A positive correlation between the overall metabolism of YM-64227 and phenacetin O-deethylation, a CYP1A2 activity marker, was observed in all the genotypes. The in vitro metabolic clearances in the T/T type of MM-1, MM-3, MM-4, and MM-5 were less than 50% lower than those in the C/C type. The anti-CYP1A1/2 antibody inhibited the metabolism of MM-1, MM-3, MM-4, and MM-5 in the C/C and C/T types. These results suggest that the formation of MM-2 and MM-3 from YM-64227 is catalyzed by CYP1A2, and that CYP1A2 contributes mainly to the subsequent metabolism of the primary metabolites of YM-64227, with the exception of MM-2. It is possible that the interindividual variability of YM-64227 with respect to the CYP1A2 deficiency polymorphism is caused by a decrease in the metabolic activities of both the unchanged drug and its metabolites.
Tenmizu
Daisuke
D
Drug Metabolism Research Laboratories, Astellas Pharma Inc, 1-8, Azusawa 1-Chome, Tokyo, Japan. daisuke.tenmizu@jp.astellas.com
Noguchi
Kiyoshi
K
Kamimura
Hidetaka
H
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D019540:Area Under Curve; D001571:Benzoflavones / Q000494:pharmacology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003510:Cyclohexanes / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D019388:Cytochrome P-450 CYP1A2 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D004285:Dogs; D005838:Genotype; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D015394:Molecular Structure; D010615:Phenacetin / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011743:Pyrimidines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology
C499820:4-cyclohexyl-1-ethyl-7-methylpyrido(2,3-d)pyrimidin-2-(1H)-one; D000911:Antibodies, Monoclonal; D001571:Benzoflavones; D003510:Cyclohexanes; D011743:Pyrimidines; C011512:alpha-naphthoflavone; D019388:Cytochrome P-450 CYP1A2; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D010615:Phenacetin