Cytochrome P450 3A4*22, PPAR-α, and ARNT polymorphisms and clopidogrel response

Abstract

Recent candidate gene studies using a human liver bank and in vivo validation in healthy volunteers identified polymorphisms in cytochrome P450 (CYP) 3A4 gene (CYP3A4*22), Ah-receptor nuclear translocator (ARNT), and peroxisome proliferator-activated receptor-α (PPAR-α) genes that are associated with the CYP3A4 phenotype. We hypothesized that the variants identified in these genes may be associated with altered clopidogrel response, since generation of clopidogrel active metabolite is, partially mediated by CYP3A activity. Blood samples from 211 subjects, of mixed racial background, with established coronary artery disease, who had received clopidogrel, were analyzed. Platelet aggregation was determined using light transmittance aggregometry (LTA). Genotyping for CYP2C19*2, CYP3A4*22, PPAR-α (rs4253728, rs4823613), and ARNT (rs2134688) variant alleles was performed using Taqman® assays. CYP2C19*2 genotype was associated with increased on-treatment platelet aggregation (adenosine diphosphate 20 μM; P=0.025). No significant difference in on-treatment platelet aggregation, as measured by LTA during therapy with clopidogrel, was demonstrated among the different genotypes of CYP3A4*22, PPAR-α, and ARNT. These findings suggest that clopidogrel platelet inhibition is not influenced by the genetic variants that have previously been associated with reduced CYP3A4 activity.

The Influence of the CYP3A4*22 Polymorphism and CYP2D6 Polymorphisms on Serum Concentrations of Aripiprazole, Haloperidol, Pimozide, and Risperidone in Psychiatric Patients

“…CYP2C19). 50 In our study, only pimozide concentrations were not significantly affected by CYP2D6 genotype but for about 5% by CYP3A4*22. This seems to fit in the findings of others, although the direction of change, namely, a decrease instead of an increase in concentrations, is unexpected and inexplicable.…”

Functional Gene Variants of CYP3A4

“…However, some studies failed to confirm an impact of CYP3A4*22 . There was no significant impact of CYP3A4*22 on clopidogrel metabolism 22 ; in addition, there was a lack of association with tacrolimus dose requirements in 216 liver‐transplanted patients 23 . Moreover, to the best of our knowledge, the influence of this CYP3A4 polymorphism on drug–drug interaction potential has not yet been investigated.…”

CDK4/6 Inhibitors in Breast Cancer Treatment: Potential Interactions with Drug, Gene, and Pathophysiological Conditions

“…Several studies tested the effect of CYP3A4*22 on PK of drugs. A significant impact of CYP3A4*22 was found on the oncologic tamoxifen [ 69 , 70 ] and sunitinib [ 71 ] and not in clopidogrel [ 72 ] and tacrolimus [ 73 ] metabolism. The relevance of CYP3A4*22 has been hypothesized to be even more enhanced in subjects having no active CYP3A5 enzyme (as most Caucasian individuals).…”