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
em En
| SES-SP, SESSP-IDPCPROD, SES-SP
| ID: biblio-1060444
Biblioteca responsável:
BR79.1
Localização: 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.
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Texto completo:
1
Bases de dados:
CONASS
/
SES-SP
Assunto principal:
RNA
/
Tratamento Farmacológico
Limite:
Aged
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Basic Clin Pharmacol Toxicol
Ano de publicação:
2017
Tipo de documento:
Article