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

Abstract

ABSTRACT: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. ␣-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 ␣-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. 4-) is a novel phosphodiesterase type 4 inhibitor. Unlike other phosphodiesterase type 4 inhibitors, YM-64227 does not induce the emetic effects that normally accompany the anti-inflammatory activity. In addition, it maintains the ability to inhibit antigen-induced airway responses. For this reason, YM-64227 promises to be a highly effective and safe drug when used as an antiasthmatic or antiinflammatory drug (Iwata et al., 1998).In previous studies, a novel CYP1A2 1117 CϾT single nucleotide polymorphism (SNP) was found in beagle dogs, which are used extensively in pharmacology and safety assessment studies (Tenmizu et al., 2004a;Mise et al., 2004a). This SNP resulted in an amino acid change from an Arg codon to a stop codon at position 373, yielding an inactive enzyme. The T-allele frequency was 0.39, which suggests that 10 to 15% of the dogs would not express the CYP1A2 protein. This CYP1A2 deficiency polymorphism causes significant changes in the pharmacokinetic profile of YM-64227 in beagle dogs (Tenmizu et al., 2006). The plasma concentrations of the unchanged drug and five of its metabolites (MM-1 to MM-5, Fig. 1) were determined after both intravenous and oral administration of YM-64227 to genotyped dogs (C/C, C/T, and T/T groups). After a single oral administration, the maximum plasma concentration and absolute bioavailability of YM-64227 in ...

Interindividual Pharmacokinetics Variability of the α4β1 Integrin Antagonist, 4-[1-[3-Chloro-4-[N′-(2-methylphenyl) ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidine-2-yl] methoxybenzoic Acid (D01-4582), in Beagles Is Associated with Albumin Genetic Polymorphisms

“…For instance, CYP2D15 and CYP1A2 have been demonstrated to be polymorphic. [13][14][15][16][17][18] Additionally, a certain population of collies has been reported to be deficient for mdr1. [19][20][21] These findings, as well as results of the present study, suggest that laboratory strains of dogs are so heterozygous that the pharmacokinetics in dogs could be varied among individuals by genetic polymorphisms, for example, drug metabolizing enzymes and transporters.…”

Canine Cytochrome P-450 Pharmacogenetics

“…Both groups used genetic testing to screen a relatively large number of their Beagle dog colonies and found that from 11 to 17% of their dogs had the homozygous mutant genotype and consequently did not express functional CYP1A2 12, 13 . The effect on the plasma drug levels of the investigational drugs was large with up to 17 times increased levels in deficient dogs (see Figure 2) 20, 21 . However animals that had at least one normal CYP1A2 copy (heterozygotes) did not have substantially different drug levels from the wild-type dogs.…”

Activity of sulfotransferase 1A1 is dramatically upregulated in patients with hepatocellular carcinoma secondary to chronic hepatitis B virus infection

“…As a probe drug, phenacetin has been extensively used to study the effects of genetic and environmental factors on CYP1A2 activity. ( 5–7 ) After the oral administration of phenacetin, its O‐deethylated metabolite acetaminophen is mostly transformed into glucuronide acetaminophen or sulfate acetaminophen by hepatic UDP‐glucuronosyltransferases (UGT) and sulfotransferase 1A1 (SULT1A1), then rapidly excreted by the kidney. ( 8,9 ) Therefore, the ratio of urine glucuronide acetaminophen to sulfate acetaminophen (RUGSA) can be applied to the detection of hepatic SULT1A1 activity.…”