IMPACT OF CLOPIDOGREL PLASMATIC LEVELS, CYP2C19 POLYMORPHISMS AND DRUG-DRUG INTERACTIONS ON CLINICAL OUTCOME IN CORONARY ARTERY DISEASE PATIENTS

The metabolism of clopidogrel is driven by 3 main hepatic isoformes of cytochrome P450 enzymes: CYP3A4, CYP2C9 and CYP2C19. Genetic polymorphisms of CYP2C19 gene and the interaction of this cytochrome with other drugs have been reported to be associated with a reduced responsiveness to clopidogrel drug prescribed to patients with coronary pathologies. Therefore, the main objective of this study was to test the effect of two genetic variants (CYP2C19*2 and CYP2C19*17) and some non-genetic factors, such as co-administration of drugs, on the cardiovascular events and plasmatic levels of clopidogrel. The studied polymorphisms were determined in 213 coronary patients taking a 300 mg loading dose of clopidogrel using polymerised chain reaction - restriction fragment length polymorphism (PCR-RFLP) method. The plasma levels of clopidogrel and its metabolites (the active form and two inactive-ones' carboxylic acid and acyl glucuronide derivatives) were determined by HPLC-MS/MS in 115 subjects (plasmatic levels could not be evaluated in all subjects due to personal and practical reasons at the time of sampling). Our results show that plasma levels of clopidogrel and its metabolites do not present significant differences between the wild-type homozygote and carriers of the CYP2C19 allele subjects. However, co-medications with simvastatin (p = 0.018), atorvastatin (p = 0.006), omeprazole (p = 0.030), metformin (p = 0.044) and insulin (p = 0.018) are the main factors affecting the clopidogrel plasmatic levels. The occurrence of death was significantly higher in patients with elevated acyl glucuronide plasma levels than those with lower plasma levels (p = 0.036). Also, patients receiving omeprazole treatment were at higher and statistically significant risk of developing cardiovascular events (p = 0.035). Based on the obtained results, we can conclude that only the non-genetic factors tested (i.e. comedications with CYP3A4 metabolized statins, proton pump inhibitor (omeprazole), oral antidiabetic (metformin) and insulin) have a significant effect on the clopidogrel inefficiency in these patients.