Balkan Journal of Medical Genetics

CO-EXISTENCE OF CYP2C19*1/*2 AND ABCB1C.3435 CT GENOTYPE HAS A POTENTIAL IMPACT ON CLINICAL OUTCOME IN CAD PATIENTS TREATED WITH CLOPIDOGREL
Nestorovska KA, Naumovska Z, Staninova Stojovska M, Sterjev Z, Dimovski A, Suturkova Lj
*Corresponding Author: Aleksandra Kapedanovska Nestorovska, PhD, Faculty of Pharmacy, Ss. Cyril and Methodius University in Skopje, Skopje, RN Macedonia, Mother Theresa str 47, 1000 Skopje, R. North Macedonia, Email address: alka@ff.ukim.edu.mk
page: 35

INTRODUCTION

Cardiovascular diseases are a leading cause of death worldwide. Coronary artery disease (CAD) is the most com- mon type of cardiovascular disease, and for those patients, Percutaneous Coronary Intervention (PCI) with stenting is the standard of care. However, in many cases post-operative patients develop major cardiovascular events (MACE) as cardiac death, myocardial infarction, stroke, and stent throm- bosis which are serious concerns (1). According to guide- lines, antiplatelet therapy is the first-line option in primary and secondary prevention of most cardiovascular diseases, followed by a thrombotic event, but despite successful treat- ment, the possibilities for recurrent ischemic events still exist (2, 3). Therefore, the use of drug-eluting stents in combina- tion with dual antiplatelet therapy of aspirin and clopidogrel significantly reduces the incidence of ischemic events and stent thrombosis in patients with CAD (4). Clopidogrel (adenosine diphosphate receptor P2Y 12 blocker) is a prodrug that needs to be converted into an active drug by several hepatic cytochrome P450 (CYP) en- zymes. For this reason, the activity of these enzymes is as- sumed as the primary determinant for therapeutic response to this drug. CYP2C19 plays a key role in the metabolic transformation. The CYP2C19 gene is highly polymorphic, and therefore the association between CYP2C19 gene vari- ants and clopidogrel efficacy appears to be clinically action- able. The presence of certain CYP2C19 polymorphisms can lead to variations in the level of functional proteins that influence the degree of clopidogrel metabolites and promote different inter-individual clopidogrel responses (5, 6). Spe- cifically, the presence of any dysfunctional CYP2C19 allele (*2,*3,*4,*5) is associated with adverse cardiovascular events, whereas the presence of CYP2C19 allele (*17) is associated with increased risk of bleeding (7, 8). Guidelines recommend the testing of CYP2C19*2 *3 and *17 in order to avoid adverse outcomes in patients with CAD treated with clopidogrel (9). According to the presence of reduced function alleles, patients are classified into two clinically significant categories: intermediate metabolizers and poor metabolizers. Due to the insufficient activity of the enzyme these patients are suggested to consider alternative P2Y12 inhibitors (ticagrelor and ticlopidine) (10). The intestinal absorption of clopidogrel is mediated by ATP-dependent drug efflux pump, and P-glycoprotein, transporting a high variety of molecules across the extra- and intra-cellular membranes. Although it is expressed mostly on the intestinal epithelial cells, an increased ex- pression can alter the bioavailability of clopidogrel. The P-glycoprotein is encoded by the ABCB1 gene located on chromosome 7 (11). Among several single nucleotide polymorphisms (SNPs) that were examined within this gene, the ABCB1 C3435T has been shown to have an ef- fect on absorption of clopidogrel (12). Namely, individuals carrying the loss of function allele variant were associated with lower levels of the active drug metabolite and were considered to have a high rate of adverse clinical outcomes (13, 14). However, recent studies have presented conflict- ing results on the association of the ABCB1 C3435T and adverse events in patients treated with clopidogrel. It is known that the pharmacodynamic response of clopidogrel can vary among individuals. Nearly 25% of patients treated with standard doses of clopidogrel experience low ex vivo inhibition of ADP-induced thrombocyte aggre- gation. The precise mechanism of resistance of clopidogrel is still unclear, although additional factors including epigenet- ics, demographics, complications and drug-drug interactions may also be involved in the response heterogeneity (15). The aim of this study was to evaluate the associa- tion between the presence of the ABCB1 C3435T and CYP2C19*2 polymorphisms and the clinical cardiovas- cular outcome in post-operative patients with coronary artery disease treated with clopidogrel.

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