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

Abstract

Clopidogrel response variability has been identified in cats. In humans, evidence suggests that variable clopidogrel active metabolite (CAM) generation is the primary explanation for clopidogrel response variability with differences in body weight, sex, and variable metabolism of clopidogrel primarily due to polymorphisms of the gene encoding cytochrome P450 (CYP) 2C19 as some proposed mechanisms. The aim of this study was to evaluate whether variation in CAM concentrations exists in healthy cats and what the cause of such variation might be. Nineteen healthy cats were given 18.75 mg clopidogrel by mouth. Blood was collected 2 hr later. Plasma CAM concentrations were measured using high performance liquid chromatography and tandem mass spectrometry. Clopidogrel metabolism was estimated by calculating CAM metabolic ratio. DNA was collected, and feline CYP2C genotyping was performed. The cats demonstrated high interindividual variation of plasma CAM concentrations.Approximately 69% of this interindividual variation was primarily explained by differences in clopidogrel metabolism as measured by CAM metabolic ratio with some influence by sex but not by weight. A single nucleotide polymorphism was identified in the feline CYP2C gene that explained in part individual differences in CAM metabolic ratio and CAM plasma concentrations. K E Y W O R D S antiplatelet, antithrombotic, Plavix, thienopyridine, thromboprophylaxis | 17 LEE Et aL. response in cats is currently unknown. The aim of this study was to evaluate whether variations in CAM concentrations exist in healthy cats given the clinically used dose of 18.75 mg clopidogrel per os andwhat the cause of such variation might be. We hypothesized that interindividual variability in CAM plasma concentrations would be present and that this variability would be influenced by variability in cat weight, sex, metabolism, and/or CYP2C genetic polymorphisms. | MATERIAL S AND ME THODS | Animal inclusion criteriaEligible client-owned cats were required to be apparently healthy, between 2 and 8 years of age, and >3.4 kg in weight. Written informed owner consent was obtained prior to participation in the study. Apparent health was determined based on history, a normal physical examination, and normal laboratory values including complete blood count, serum biochemistry panel, urinalysis, negative feline leukemia virus and feline immunodeficiency virus testing, and a normal echocardiogram. All blood work and urinalyses were performed by the Washington State University Clinical Pathology Laboratory.All echocardiograms were performed by a single investigator (PML).Conventional 2D, M-mode, and Doppler examinations were performed using an echocardiographic system and transducers ranging from 4 to 10 MHz. This study was approved by the Washington State University Institutional Animal Care and Use Committee.

Assessment of P2Y12 Inhibition by Clopidogrel in Feline Platelets Using Flow Cytometry Quantification of Vasodilator-Stimulated Phosphoprotein Phosphorylation

“…The proportion of clopidogrel non-responders in this study is also similar to a different population of cats with the genetic predisposition to HCM (11,22,23). Based on a study by Lee et al (23), this pharmacodynamic variability could be explained by nonsynonymous single nucleotide polymorphisms in the feline CYP2C genes, responsible for encoding the cytochrome P isoenzymes for metabolizing clopidogrel to its active metabolite. However, no studies to date have documented the phenotypes of these mutations in cats based on clopidogrel-specific platelet function assays.…”

“…The fact that male cats are nearly twice as likely to be affected by CATE as female cats suggests that gender differences in platelet function may occur in cats (3,26). Another study also found that female cats had higher clopidogrel active metabolite than male cats after a single dose of clopidogrel highlighting the gender differences in cytochrome P450 activity (23). Future studies with a population of cats that reflects the signalment of cats at risk of CATE are needed.…”

Abnormal platelet activity in dogs and cats – impact and measurement

“…High interindividual variability in clopidogrel plasma levels has been reported, although this was considered mostly secondary to differences in metabolism (Lee et al . ). The results of the FAT CAT trial (Hogan et al.…”

“…There is no published prevalence of drug resistance in cats. High interindividual variability in clopidogrel plasma levels has been reported, although this was considered mostly secondary to differences in metabolism (Lee et al 2019). The results of the FAT CAT trial (Hogan et al 2015) did suggest that clopidogrel is superior to aspirin in reducing the risk of recurrent aortic thromboembolism.…”

Genetic Polymorphisms Impact Response to Clopidogrel in Feline Hypertrophic Cardiomyopathy

“…[15][16][17][18][19][20][21][22][23] In cats, non-synonymous single nucleotide polymorphisms (SNPs) in the P2RY1 and P2RY12 genes and in the feline CYP2C gene (CYP2C41) were recently reported. 24,25 One study also reported that one of the variants in the feline CYP2C41 gene, CYP2C41:H231R, was associated with increased clopidogrel active metabolite (CAM) concentration after administration of a single dose of clopidogrel in healthy cats. This nding supports the contention that these SNPs could lead to clopidogrel resistance in cats.…”