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- Title
ABCC3 Polymorphisms and mRNA Expression Influence the Concentration of a Carboxylic Acid Metabolite in Patients on Clopidogrel and Aspirin Therapy.
- Authors
Luchessi, André Ducati; Concheiro, Marta; Germano, Juliana de Freitas; Silbiger, Vivian Nogueira; Bortolin, Raul Hernandes; Cruz, Angelines; Quintela, Oscar; Brion, Maria; Carracedo, Angel; Iñiguez, Andres; Bravo, Marisol; López‐Rivadulla, Manuel; Hirata, Rosario Dominguez Crespo; Sousa, Amanda Guerra Moraes Rego; Hirata, Mario Hiroyuki
- Abstract
Acetylsalicylic acid (ASA) and clopidogrel combined therapy has been reported to be beneficial in patients with acute coronary syndrome ( ACS). Antiplatelet drug resistance, especially to clopidogrel, is a multifactorial phenomenon that affects a large number of ACS patients. The genetic contribution to this drug response is not fully elucidated. We investigated the relationship of ABC-type efflux subfamily C member 3 ( ABCC3) polymorphisms and mRNA expression with plasma concentrations of clopidogrel, salicylic acid ( SA) and a carboxylic acid metabolite ( CAM). Clopidogrel, CAM and SA plasma concentrations were measured simultaneously by liquid chromatography-tandem mass spectrometry ( LCMS/ MS) from 83 ACS patients undergoing percutaneous coronary intervention. ABCC3 (rs757421, rs733392 and rs739923) and CYP2C19*2 (rs4244285) polymorphisms as well as mRNA expression were evaluated. A positive correlation was found between CAM concentrations and ABCC3 mRNA expression ( r = 0.494, p < 0.0001). Patients carrying genotype AA (rs757421 variant) had higher CAM concentrations and ABCC3 mRNA expression as compared to those of GG + GA carriers ( p = 0.017). A multiple linear regression analysis revealed that ABCC3 mRNA expression ( p = 0.017), rs757421 AA genotype ( p = 0.001), blood collection time ( p = 0.018) and clopidogrel dose ( p = 0.001) contributed to the concentration of CAM. No associations were observed for the CYP2C19*2 polymorphism. These results suggest that up-regulation of ABCC3 mRNA expression leads to increased plasma CAM levels through MRP3-mediated cell efflux. The ABCC3 rs757421 polymorphism may contribute to gene expression. Therefore, ABCC3 may be a potential biomarker for the response to clopidogrel.
- Subjects
MESSENGER RNA; CARBOXYLIC acids; CLOPIDOGREL; ASPIRIN; TREATMENT of acute coronary syndrome; METABOLITES
- Publication
Basic & Clinical Pharmacology & Toxicology, 2017, Vol 120, Issue 5, p466
- ISSN
1742-7835
- Publication type
Article
- DOI
10.1111/bcpt.12703