title: ABCC3 Polymorphisms and mRNA Expression Influence the Concentration of a Carboxylic Acid Metabolite in Patients on Clopidogrel and Aspirin Therapy.
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.
authors.affiliation: School of Pharmaceutical Science, University of Sao Paulo, Sao Paulo, Brazil.|Department of Clinical and Toxicological Analysis, Federal University of Rio Grande do Norte, Natal, Brazil.
authors.forename: André Ducati
authors.initials: AD
authors.lastname: Luchessi
authors.affiliation: Luis Concheiro Institute of Forensic Sciences, University of Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Concheiro
authors.affiliation: School of Pharmaceutical Science, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Juliana de Freitas
authors.initials: JF
authors.lastname: Germano
authors.affiliation: Department of Clinical and Toxicological Analysis, Federal University of Rio Grande do Norte, Natal, Brazil.
authors.forename: Vivian Nogueira
authors.initials: VN
authors.lastname: Silbiger
authors.affiliation: Department of Clinical and Toxicological Analysis, Federal University of Rio Grande do Norte, Natal, Brazil.
authors.forename: Raul Hernandes
authors.initials: RH
authors.lastname: Bortolin
authors.affiliation: Luis Concheiro Institute of Forensic Sciences, University of Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: Angelines
authors.initials: A
authors.lastname: Cruz
authors.affiliation: Department of Madrid, National Institute of Toxicology and Forensic Science, Madrid, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Quintela
authors.affiliation: Genetics of Cardiovascular and Ophthalmological Diseases, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.|Genomic Medicine, University of Santiago de Compostela, IDIS, CIBERER, Santiago de Compostela, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Brion
authors.affiliation: Genomic Medicine, University of Santiago de Compostela, IDIS, CIBERER, Santiago de Compostela, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.affiliation: Cardiology Service, Alvaro Cunqueiro Hospital, Vigo, Spain.
authors.forename: Andres
authors.initials: A
authors.lastname: Iñiguez
authors.affiliation: Cardiology Service, Alvaro Cunqueiro Hospital, Vigo, Spain.
authors.forename: Marisol
authors.initials: M
authors.lastname: Bravo
authors.affiliation: Luis Concheiro Institute of Forensic Sciences, University of Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: López-Rivadulla
authors.affiliation: School of Pharmaceutical Science, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Rosario Dominguez Crespo
authors.initials: RD
authors.lastname: Hirata
authors.affiliation: Dante Pazzanese Institute of Cardiology, Sao Paulo, Brazil.
authors.forename: Amanda Guerra Moraes Rego
authors.initials: AG
authors.lastname: Sousa
authors.affiliation: School of Pharmaceutical Science, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Mario Hiroyuki
authors.initials: MH
authors.lastname: Hirata
mesh_terms: D054058:Acute Coronary Syndrome / Q000628:therapy; D000368:Aged; D001241:Aspirin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D002264:Carboxylic Acids / Q000378:metabolism; D002853:Chromatography, Liquid / Q000379:methods; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D062645:Percutaneous Coronary Intervention / Q000379:methods; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D020156:Salicylic Acid / Q000378:metabolism; D053719:Tandem Mass Spectrometry / Q000379:methods; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D001241:Aspirin; D002264:Carboxylic Acids; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010975:Platelet Aggregation Inhibitors; D012333:RNA, Messenger; D020156:Salicylic Acid; D013988:Ticlopidine; C114462:multidrug resistance-associated protein 3