ABCC3 Polymorphisms and mRNA Expression Influence the / Concentration of a Carboxylic Acid Metabolite in Patients on / Clopidogrel and Aspirin Therapy
Basic Clin Pharmacol Toxicol
; 120(5): 466-474, 2017. graf, tab
Article
in English
| Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP
| ID: biblio-1060444
Responsible library:
BR79.1
Localization: BR79.1
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.
Full text:
Available
Collection:
National databases
/
Brazil
Database:
Sec. Est. Saúde SP
/
SESSP-IDPCPROD
Main subject:
RNA
/
Drug Therapy
Limits:
Aged
/
Female
/
Humans
/
Male
Language:
English
Journal:
Basic Clin Pharmacol Toxicol
Year:
2017
Document type:
Article
Institution/Affiliation country:
Alvaro Cunqueiro Hospital/ES
/
Dante Pazzanese of Cardiology/BR
/
Federal University of Rio Grande do Norte/BR
/
Institute of Santiago de Compostela (IDIS)/ES
/
Luis Concheiro Institute of Forensic Sciences/ES
/
National Institute of Toxicology and Forensic Science/ES
/
School of Pharmaceutical Science/BR
/
University of Santiago de Compostela/ES