Impact of common ABCB1 polymorphism on pharmacokinetics and pharmacodynamics of clopidogrel and its metabolites. (28th November 2014)

• Record Type: Journal Article
• Authors: Karaźniewicz‐Łada, M.; Danielak, D.; Rubiś, B.; Burchardt, P.; Komosa, A.; Lesiak, M.; Główka, F.
• Is Part Of: Journal of clinical pharmacy and therapeutics. Volume 40:Number 2(2015:Apr.)
• Page Start: 226
• Page End: 231
• Publication Date: 2014-11-28
• Subjects: Clinical pharmacology -- Periodicals; Chemotherapy -- Periodicals; 615
• DOI: 10.1111/jcpt.12236
• Languages: English
• ISSNs: 0269-4727

Abstract

<abstract abstract-type="main" id="jcpt12236-abs-0001"> <title>Summary</title> <sec id="jcpt12236-sec-0001" sec-type="section"> <title>What is known and objective</title> <p>The reasons of clopidogrel (CLP) resistance are still unclear. The response to CLP may be influenced by both genetic and non‐genetic factors. Among genetic factors, common polymorphisms in the gene coding glycoprotein‐P (P‐gp, MDR1 and ABCB1) are considered as potential determinants of the efficacy of CLP treatment. The aim of this study was to evaluate the influence of <italic>ABCB1</italic> 3435C>T genetic polymorphism on the pharmacokinetics and pharmacodynamics of CLP and its metabolites: diastereoisomers of thiol metabolite (the inactive H3 and the active H4) and inactive carboxylic derivative.</p> </sec> <sec id="jcpt12236-sec-0002" sec-type="section"> <title>Methods</title> <p>The study group included 42 patients undergoing elective coronary angiography and percutaneous coronary intervention. The plasma concentrations of CLP and its metabolites were measured by a validated HPLC‐MS/MS method. Whole‐blood aggregation was determined with Multiplate analyzer. For evaluation of <italic>ABCB1</italic> 3435C>T polymorphism, PCR‐RFLP method was applied.</p> </sec> <sec id="jcpt12236-sec-0003" sec-type="section"> <title>Results and discussion</title> <p>It was found that Exposition to the unchanged CLP, measured by AUC<sub>0–<italic>t</italic></sub> of the drug, was significantly lower (<italic>P </italic>=<italic> </italic>0·012) in TT homozygotes comparing to that observed in CC and CT genotypes, although no correlation was found between platelet aggregation and <italic>ABCB1</italic> genetic polymorphism.</p> </sec> <sec id="jcpt12236-sec-0004" sec-type="section"> <title>What is new and conclusion</title> <p>Our findings show that the presence of 3435C>T allele has an impact on CLP pharmacokinetics but not on the drug pharmacodynamics. Therefore, the 3435C>T genotype may not be the primary determinant influencing the pharmacokinetics of the active H4 metabolite and antiplatelet effect of the drug.</p> </sec> </abstract>