Impact of selected genetic factors on clopidogrel inactive metabolite level and antiplatelet response in patients after percutaneous coronary intervention

• Published in: Pharmacological reports Vol. 73; no. 2; pp. 583 - 593
• Main Authors: Adamiak-Giera, Urszula, Czerkawska, Anna, Olędzki, Szymon, Kurzawski, Mateusz, Safranow, Krzysztof, Jastrzębska, Maria, Gawrońska-Szklarz, Barbara
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.04.2021
• Subjects: Aged; Alleles; Chromatography, High Pressure Liquid; Clopidogrel - administration & dosage; Clopidogrel - pharmacokinetics; Clopidogrel - pharmacology; Cytochrome P-450 CYP2C19 - genetics; Drug Safety and Pharmacovigilance; Female; Humans; Male; Medicine; Middle Aged; Percutaneous Coronary Intervention - methods; Pharmacotherapy; Pharmacy; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - administration & dosage; Platelet Aggregation Inhibitors - pharmacokinetics; Platelet Aggregation Inhibitors - pharmacology; Polymorphism, Genetic; Prospective Studies; Ticlopidine - analogs & derivatives; Ticlopidine - pharmacokinetics; Clopidogrel inactive metabolite; Genetic polymorphisms; Concentration
• ISSN: 1734-1140; 2299-5684; 2299-5684
• DOI: 10.1007/s43440-020-00197-w

Background and objective Clopidogrel is frequently used as part of optimal dual antiplatelet therapy in high-bleeding risk patients with the acute coronary syndrome. The concentration of the inactive carboxylic acid metabolite of clopidogrel might be useful to evaluate the response to clopidogrel therapy. Therefore, we sought to correlate the inhibition of platelet aggregation with the plasma level of the inactive metabolite of clopidogrel in patients after percutaneous coronary interventions (PCI) and their associations with the most frequently studied genetic polymorphisms. For this purpose, the fast and simple HPLC method for determining the concentration of the inactive metabolite was developed. Methods The effect of CYP2C19 , CYP3A4/5 , ABCB1 and PON1 genes on the plasma inactive metabolite concentration of clopidogrel and the platelet aggregation was investigated in 155 patients before and after PCI. Results The concentration of the inactive metabolite of clopidogrel was not significantly different in the intermediate metabolizers (IM) of CYP2C19 compared with extensive metabolizers (EM) both before and after PCI, while inhibition of platelet aggregation was found to be significantly better in EM than in IM. The presence of the A allele at position 2677 in the ABCB1 gene was associated with a significantly lower concentration of inactive metabolite of clopidogrel before PCI. Conclusion The CYP2C19*2 allele was associated with decreased platelet reactivity during clopidogrel therapy before and after PCI. Simultaneous determination of platelet aggregation and concentration of the inactive clopidogrel metabolite may be useful in clinical practice to find the cause of adverse effects or insufficient treatment effect in patients chronically treated with clopidogrel.