IMPACT OF CLOPIDOGREL PLASMATIC LEVELS, CYP2C19
POLYMORPHISMS AND DRUG-DRUG INTERACTIONS ON CLINICAL
OUTCOME IN CORONARY ARTERY DISEASE PATIENTS
RANIA ABDELHEDI 1, NAJLA KHARRAT 1, MARTIN MAURER 2, NOUHA BOUAYED ABDELMOULA 3, LEILA ABID 4, LOBNA LAROUSSI 4, SAMIR KAMMOUN 4, TAREK REBAI 3, AHMED REBAI 1, LUIGI SILVESTRO 2*
1Laboratory of Molecular and Cellular Screening Processes, Centre of Biotechnology of Sfax, Route Sidi Mansour, 3018,
University of Sfax, Sfax, Tunisia
23S-Pharmacological Consultation and Research GmbH, Koenigsbergerstrasse 1, 27243, Harpstedt, Germany
3Department of Histology, Faculty of Medicine of Sfax, Majida Boulila Avenue 3028 Sfax, Tunisia
4Cardiology service, Hedi Chaker University Hospital Sfax, El Ain road, 3029 Sfax, Tunisia
*corresponding author: Dreispharmasl@aol.com
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Abstract:
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.

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