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High interindividual variability in plasma clopidogrel active metabolite concentrations in healthy cats is associated with sex and cytochrome P450 2C genetic polymorphism

Lee PM, Faus MCL, Court MH. High interindividual variability in plasma clopidogrel active metabolite concentrations in healthy cats is associated with sex and cytochrome P450 2C genetic polymorphism. J Vet Pharmacol Ther. 2019 Jan;42(1):16-25.

Thromboembolic disease (Feline Aortic Thromboembolism; FATE) is a frequently seen complication of heart disease in domestic cats. Clopidogrel has become the most popular drug for primary and secondary prevention of this condition due to its in vivo and in vitro efficacy at decreasing platelet aggregation. In humans, a variable response is seen with clopidogrel therapy that is due in large part to differences in the activity of the gene CYP2C (a member of the cytochrome P450 family). CYP2C is responsible for a portion of the conversion of the prodrug clopidogrel to its active form CAM-D via the unstable intermediate CAM. Previous data from multiple studies have indicated that there is a variable efficacy of clopidogrel in cats, though the reason for this is unknown.

The purpose of this study was to confirm if variation in CAM exists in cats after a standard dose of 18.75mg clopidogrel PO, and to determine the potential genetic and signalment factors that could explain this variation. The study was designed as a prospective trial.

8 healthy, client owned cats were recruited into the study. Cats had a normal physical exam, serum biochemistry, CBC, urinalysis, and echocardiogram. 19 cats were recruited into the study and met all inclusion criteria. 10 were neutered males and 9 spayed females.

Cats were fasted overnight and administered precisely 18.75mg clopidogrel (equivalent to 14 of a standard 75mg tablet). Blood was collected 2h after administration, and cheek swabs were collected for DNA isolation. Plasma clopidogrel, CAM-D, and clopidogrel carboxylic acid levels were determined. Clipidogrel Metabolic Ratio was calculated as an indicator of the conversion of clopidogrel to the active form

The gene for CYP2C was sequenced in each of the cats and single nucleotide polymorphisms (SNPs) identified encoding missense mutations.

Male cats were found to have significantly higher levels of CAM-D than females, thought he metabolic ratio was not different. This suggests that male cats do not have a greater conversion of clopidogrel to CAM-D, but have higher blood levels of CAM-D.

Cats homozygous for the genotype CYP2C-3 had 3 fold increased CAM-D and metabolic ratio values than cats with other variants. This suggests cats with this genotype have a more effective conversion of clopidogrel to CAM-D.

The authors conclude that 69% of the variation in CAM-D was due to weight, sex, and CAM-D formation. 36% of total variability was due to CAM-D formation, and 28% was due to sex. Weight was not a major influencer of CAM-D level, suggesting that a fixed dose per cat is an effective strategy, rather than adjustment based on weight. They further posit that variations in CYP2C may lead to differing clopidogrel metabolic ratios in cats.

It is important to note that the clinical relevance of the differing CAM-D concentration was not determined by this study, and so further work should be done to determine if platelet aggregation is significantly influenced. Multiple doses and sampling at different time points may also reveal differences in metabolic parameters.

The findings of this study suggest that the efficacy of clopidogrel may be affected by a variety of factors, especially the sex of the cat and variants in the CYP2C gene. In male cats and cats with an identified gene variant, alternative antiplatelet or anticoagulant agents should be considered. Further work should be done investigating these effects in a multi-dose setting, as well as working to identify if there is a difference in clinical outcome for male or CYP2C variant cats.  (MRK)

See Also

Backman, J. D., O’Connell, J. R., Tanner, K., Peer, C. J., Figg, W. D., Spencer, S. D., … Lewis, J. P. (2017). Genome‐wide analysis of clopidogrel active metabolite levels identifies novel variants that influence antiplatelet response. Pharmacogenetics and Genomics27(4), 159–163.

Hogan, D. F., Fox, P. R., Jacob, K., Keene, B., Laste, N. J., Rosenthal, S., … Weng, H. Y. (2015). Secondary prevention of cardiogenic arterial thromboembolism in the cat: The double‐blind, randomized, positive‐controlled feline arterial thromboembolism; clopidogrel vs. aspirin trial (FAT CAT). Journal of Veterinary Cardiology17(Suppl 1), S306–S317. 

Brainard, B. M., Kleine, S. A., Papich, M. G., & Budsberg, S. C. (2010). Pharmacodynamic and pharmacokinetic evaluation of clopidogrel and the carboxylic acid metabolite SR 26334 in healthy dogs. American Journal of Veterinary Research71(7), 822–830.