Influence of CYP450 Enzymes, CES1, PON1, ABCB1, and P2RY12 Polymorphisms on Clopidogrel Response in Patients Subjected to a Percutaneous Neurointervention

• Published in: Clinical therapeutics 2019-06, Vol.41 (6), p.1199-1212.e2
• Main Authors: Saiz-Rodríguez, Miriam, Belmonte, Carmen, Caniego, José Luis, Koller, Dora, Zubiaur, Pablo, Bárcena, Eduardo, Romero-Palacián, Daniel, Eugene, Andy R., Ochoa, Dolores, Abad-Santos, Francisco
• Format: Article
• Language: English
• Subjects: Absorption; Aged; Alleles; Antiplatelet therapy; Arteries; Aryldialkylphosphatase - genetics; ATP Binding Cassette Transporter, Subfamily B - genetics; Bleeding; Carboxylesterase; Carboxylic Ester Hydrolases - genetics; Cerebrovascular Disorders - surgery; CES1; Clopidogrel; Clopidogrel - pharmacokinetics; Clopidogrel - therapeutic use; CYP1A2 protein; CYP2C19; Cytochrome; Cytochrome P-450 Enzyme System - genetics; Cytochrome P450; Cytochromes; Deoxyribonucleic acid; DNA; Drug dosages; Enzymes; Female; Genes; Genotype & phenotype; Genotyping; Glycoproteins; Haplotypes; Hemorrhage; Hemorrhage - drug therapy; Hemorrhage - epidemiology; Hemorrhage - genetics; Hemorrhage - prevention & control; Humans; Implants; Ionization; Ischemia; Ischemia - drug therapy; Ischemia - epidemiology; Ischemia - genetics; Ischemia - prevention & control; Male; Mass spectrometry; Mass spectroscopy; Metabolism; Metabolites; Middle Aged; Multivariate analysis; P-Glycoprotein; P2Y12; Paraoxonase; Pharmacology; Platelet aggregation; Platelet Aggregation Inhibitors - pharmacokinetics; Platelet Aggregation Inhibitors - therapeutic use; Polymerase chain reaction; PON1; Receptors, Purinergic P2Y12 - genetics; Retrospective Studies; Risk analysis; Risk factors; Surgical implants; Therapy; Thromboembolism; Values; Vertebrae
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2019.04.037

Clopidogrel is a thienopyridine prodrug that inhibits platelet aggregation. It is prescribed to prevent atherothrombotic and thromboembolic events in patients receiving a stent implant in carotid, vertebral, or cranial arteries. The influence of cytochrome P-450 (CYP) 2C19 on the response to clopidogrel has been widely studied; however, the effect of other genes involved in clopidogrel absorption and metabolism has not been established in this cohort of patients. This observational retrospective study assessed the antiplatelet response and the prevalence of hemorrhagic or ischemic events after percutaneous neurointervention in clopidogrel-treated patients, related to 35 polymorphisms in the genes encoding the clopidogrel-metabolizing enzymes (CYP2C19, CYP1A2, CYP2B6, CYP2C9, CYP2C9, CYP3A4, CYP3A5, carboxylesterase-1 [CES1], and paraoxonase-1 [PON1]), P-glycoprotein transporter (ABCB1), and platelet receptor P2Y12. Polymorphisms were analyzed by quantitative real-time polymerase chain reaction and matrix-assisted laser desorption/ionization–time-of-flight mass spectrometry. Antiplatelet response was documented with the VerifyNow system (Accriva, San Diego, California). We confirmed that CYP2C19 is the most important enzyme involved in clopidogrel response. The carriage of the CYP2C19*2 allele was strongly associated with hyporesponse to clopidogrel, while the CYP2C19*17 allele was a protective factor for the development of ischemic events (odds ratio = 0.149; P = 0.002) but a risk factor for bleeding (odds ratio = 3.60; P = 0.038). Patients carrying ABCB1 mutated alleles showed lower aggregation values, suggesting that clopidogrel absorption is influenced by P-glycoprotein. In fact, the percentage of responders was significantly higher in the group carrying the mutated haplotype compared to the wild type (80.8% vs 43.3%; P = 0.009). Patients with the CES1 G143E C/T genotype showed a considerably lower, aggregation value versus wild-type patients, although the difference was not significant likely due to the small sample size (59.0 [21.2] vs 165.2 [86.0] PRU; P = 0.084), which suggests an increased active metabolite formation. No relationship was found between polymorphisms in other CYP genes, PON1, or P2RY12 and response to clopidogrel in patients subjected to neurointervention procedures. Therapeutic guidelines recommend that CYP2C19 intermediate and poor metabolizers with acute coronary syndromes undergoing percutaneous coronary intervention receive an a