The impact of CYP3A5*1/*3, PIA1/A2 and T744C polymorphisms on clopidogrel and acetylsalicylic acid response variability in Mexican population

Isordia‐Salas, Irma; Olalde-Román, Marcos Jaciel; Santiago-Germán, David; Peña, Norma Corona de la; Valencia-Sánchez, Jesús Salvador

doi:10.1016/j.thromres.2012.06.024

Cited by 11 publications

(9 citation statements)

References 24 publications

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“…In accordance with our study, no association between CYP3A4*1G and CYP3A5*3 and clopidogrel PK and/or PD was observed elsewhere. [36][37][38][39][40][41] On the contrary, CYP3A4*1G allele was reported to be associated with better clopidogrel responsiveness in Spanish patients with stable coronary artery disease 42) and in Chinese patients with ischemic stroke. 43) Evidence also revealed that CYP3A5*3 was associated with clopidogrel response and clinical outcomes.…”

Section: Discussionmentioning

confidence: 97%

No Effect of SLCO1B1 and CYP3A4/5 Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Male Subjects

et al. 2017

Biological & Pharmaceutical Bulletin

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Ticagrelor is a direct-acting P2Y12 receptor antagonist. It is rapidly absorbed and partly metabolized to the active metabolite AR-C124910XX by CYP3A4 and CYP3A5. Three genetic loci (SLCO1B1, CYP3A4, and UGT2B7) were reported to affect ticagrelor pharmacokinetics. This study aimed to investigate the possible effects of SLCO1B1 and CYP3A4/5 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese male volunteers. Eighteen healthy male volunteers who participated in pharmacogenetics study of ticagrelor were genotyped for SLCO1B1 rs113681054, SLCO1B1*5 (rs4149056), CYP3A4*1G (rs2242480), and CYP3A5*3 (rs776746). All subjects received a single 180 mg loading dose of ticagrelor and then series blood samples were collected from 0 to 48 h. Plasma concentrations of ticagrelor and AR-C124910XX were determined by the high performance liquid chromatography-tandem mass spectrometry method. Inhibition in platelet aggregation (IPA) was assessed and the area under the time-effect curve (AUEC) for the IPA was calculated as pharmacodynamic parameters. No significant difference in ticagrelor pharmacokinetics among genotypes of the two genes was observed. The AUEC did not differ significantly among genotypes of candidate single nucleotide polymorphisms (SNPs). Our data suggest that common genetic variants in SLCO1B1 and CYP3A4/5 may have no effect on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese volunteers. Key words ticagrelor; pharmacokinetics; pharmacodynamics; SLCO1B1; CYP450Ticagrelor is the first reversible P2Y12 receptor inhibitor that provides faster onset/offset of pharmacological action and more consistent platelet inhibition compared to clopidogrel. It is recommended for combination therapy with aspirin in patients presenting with acute coronary syndrome (ACS) and undergoing percutaneous coronary intervention (PCI). In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor was observed to reduce the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke, but showed similar rates of major bleeding compared with clopidogrel. 1)As compared with clopidogrel, ticagrelor does not require metabolic activation to exert its antiplatelet effects. The major active metabolite of ticagrelor, AR-C124910XX (ARC), is formed via the hepatic CYP enzyme, CYP3A4 and CYP3A5.2) ARC is present in the blood at about 30-40% of the concentration of ticagrelor with a similar antiplatelet activity. Like other antiplatelet drugs, ticagrelor also shows interindividual variation in platelet inhibitory response in patients with ACS.3)At present, no genetic determinants for the ticagrelor pharmacodynamics (PD) are known, [4][5][6] although several genetic loci (SLCO1B1, UGT2B7, and CYP3A4) were reported to affect the pharmacokinetics (PK) of ticagrelor in Caucasian patients with ACS. 7) However, single nucleotide polymorphisms (SNPs) in the PK related genes showed no effects on efficacy or safety of ticagrelor. 7) Our previous studies r...

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Section: Discussionmentioning

confidence: 97%

No Effect of SLCO1B1 and CYP3A4/5 Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Male Subjects

et al. 2017

Biological & Pharmaceutical Bulletin

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“…Since genetic polymorphisms in the P2Y 12 receptor were not associated with HTPR, we sought to deter- 36) and Isordia-Salas. 37) Hence, genetic screening for GPIIIa polymorphisms may not be warranted, as they are less likely to be associated with HTPR.…”

Section: Discussionmentioning

confidence: 99%

Genotype Frequencies of CYP2C19, P2Y12 and GPIIIa Polymorphisms in Coronary Heart Disease Patients of Han Ethnicity, and Their Impact on Clopidogrel Responsiveness

et al. 2016

Int. Heart J.

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“…Studies that were not suitable for inclusion in the metaanalysis included 300 healthy subjects and 354 with cardiovascular disease (Table 2) [12,[36][37][38][39][40][41][42][43][44][45][46][47][48]. Conclusions from the studies were similarly heterogeneous, with half of the studies suggesting an association between carriage of the PlA2 allele and aspirin resistance [39,40,43,44,[46][47][48].…”

Section: Figurementioning

confidence: 99%

“…antagonists [24,30,39,41,[49][50][51][52][53]. All participants in these studies received in vivo clopidogrel except for a single study investigating in vivo ticagrelor [53].…”

Section: P2y12 Receptor Antagonistsmentioning

confidence: 99%

“…Six studies did not contain adequate data for statistical analysis and are summarized in Table 3 [24,39,41,49,50,53]. Of these studies, one reported a positive association between carriage of the PlA2 allele and clopidogrel resistance [49], one reported a negative association [50] and the remainder failed to identify any association.…”

Section: P2y12 Receptor Antagonistsmentioning

confidence: 99%

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The PlA1/A2 polymorphism of glycoprotein IIIa in relation to efficacy of antiplatelet drugs: a systematic review and meta-analysis

Floyd

Ferro

2014

Br J Clin Pharmacol

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AIMThe PlA1/A2 polymorphism of glycoprotein IIIa (GPIIIa) has been associated with both antiplatelet drug resistance and increased cardiovascular events. The aim of this study was to conduct the first meta-analysis investigating the association between carriage of the PlA2 allele and resistance to currently licensed antiplatelet drugs. METHODSElectronic databases (MEDLINE and EMBASE) were searched for all articles evaluating genetic polymorphisms of GPIIIa. For studies where antiplatelet resistance was measured using validated techniques, pooled odds ratios (ORs) were calculated using fixed effects and random effects models. RESULTSSixteen studies were eligible for statistical analysis and included 1650 PlA1 homozygous subjects and 668 carriers of the PlA2 allele. For carriers of the PlA2 allele, OR 0.924 (n = 2318; 95% CI 0.743, 1.151; P = 0.481) was observed for resistance to any antiplatelet drug, OR 0.862 (n = 2085; 95% CI 0.685, 1.086; P = 0.208) for resistance to aspirin and OR 1.429 (n = 233; 95% CI 0.791, 2.582; P = 0.237) for resistance to clopidogrel. In the aspirin cohort, sub-group analysis revealed no statistical association in either healthy subjects or those with cardiovascular disease. PlA2 carriage was marginally associated with aspirin sensitivity using the fixed effects model when identified by the PFA-100 assay (n = 1151; OR 0.743, 95% CI 0.558, 0.989; P = 0.041) but with significant heterogeneity (I 2 = 55%; P = 0.002). Significance was lost with analysis using a random effects model. CONCLUSIONSThe totality of published data does not support an association between carriage of the PlA2 allele and antiplatelet drug resistance. Significant heterogeneity indicates the need for larger studies using validated and standardized assays.

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The impact of CYP3A51/3, PIA1/A2 and T744C polymorphisms on clopidogrel and acetylsalicylic acid response variability in Mexican population

Cited by 11 publications

References 24 publications

No Effect of <i>SLCO1B1</i> and <i>CYP3A4/5</i> Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Male Subjects

No Effect of <i>SLCO1B1</i> and <i>CYP3A4/5</i> Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Male Subjects

Genotype Frequencies of CYP2C19, P2Y<sub>12</sub> and GPIIIa Polymorphisms in Coronary Heart Disease Patients of Han Ethnicity, and Their Impact on Clopidogrel Responsiveness

The PlA1/A2 polymorphism of glycoprotein IIIa in relation to efficacy of antiplatelet drugs: a systematic review and meta-analysis

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