Contribution of Gene Sequence Variations of the Hepatic Cytochrome P450 3A4 Enzyme to Variability in Individual Responsiveness to Clopidogrel

Abstract

Objectives-Metabolic activity of cytochrome P450 (CYP) 3A4 has been associated with clopidogrel response variability.Because metabolic activity of CYP3A4 is genetically regulated, we hypothesized that genetic variations of this enzyme may contribute to clopidogrel response variability. Methods and Results-The CYP3A4*1B, CYP3A4*3, IVS7ϩ258AϾG, IVS7ϩ894CϾT, and IVS10ϩ12GϾA polymorphisms of the CYP3A4 gene were assessed in 82 patients in a steady phase of clopidogrel therapy. Glycoprotein (platelet glycoprotein (GP) IIb/IIIa receptor activation and platelet aggregation were assessed. A cohort of 45 clopidogrel-naïve patients was studied to determine the modulating effects of these polymorphisms after loading dose (300 mg) administration. Only the IVS7ϩ258AϾG, IVS7ϩ894CϾT, and IVS10ϩ12GϾA polymorphisms were sufficiently polymorphic. During the steady phase of clopidogrel treatment, IVS10ϩ12A allele carriers had reduced GP IIb/IIIa activation (Pϭ0.025) and better responsiveness (Pϭ0.02); similarly, clopidogrel-naïve patients carriers of the IVS10ϩ12A allele had reduced GP IIb/IIIa activation during the first 24 hours after a loading dose (Pϭ0.025), increased platelet inhibition (Pϭ0.006), and a more optimal drug response (Pϭ0.003). This polymorphism did not influence platelet aggregation profiles. No association was observed between the other polymorphisms and clopidogrel responsiveness. Key Words: clopidogrel Ⅲ platelet Ⅲ polymorphism T reatment with clopidogrel is associated with a broad variability in antiplatelet effects. [1][2][3][4] This may be partly attributed to the levels of clopidogrel's active metabolite. 5 Clopidogrel in fact is an inactive pro-drug that requires oxidation by the hepatic cytochrome P450 3A4 (CYP3A4) to generate an active metabolite. 6 -7 The active metabolite of clopidogrel inhibits platelet activation through an irreversible blockage of the platelet adenosine diphosphate (ADP) P2Y 12 receptor. The P2Y 12 receptor inhibits adenylyl cyclase and in turn decreases platelet cAMP (cAMP) levels and cAMPmediated phosphorylation of the vasodilator-stimulated phosphoprotein, critical for inhibition of glycoprotein (GP) IIb/ IIIa receptor activation. 8 Conclusions-The See page 1681Drugs that are substrates or inhibit CYP3A4 can potentially interfere with the conversion of clopidogrel into its active metabolite. 9 -11 Accordingly, the metabolic activity of the CYP3A4 enzyme, which varies considerably among individuals, 12 has shown to influence platelet reactivity after a clopidogrel loading dose. 13 Because genetic predisposition is the major determinant of heterogeneity in metabolic activity of the CYP3A4 enzyme, 12,14 -15 we hypothesized that single-nucleotide polymorphisms (SNPs) of CYP3A4 may account for interindividual variability of platelet reactivity in patients treated with clopidogrel. In the present study we examined the influence of SNPs of the CYP3A4 enzyme on platelet reactivity and responsiveness to clopidogrel in patients with coronary artery disease. Materials and Methods Detail...

Associations of CYP3A4, NR1I2, CYP2C19 and P2RY12 polymorphisms with clopidogrel resistance in Chinese patients with ischemic stroke

“…This mutant genotype was correlated with a higher CYP3A metabolic activity, thus increasing the formation of metabolites, particularly for prodrugs, which are activated through biotransformation via CYP3A [30] . In addition, there is evidence of an association between the presence of CYP3A4*1G and clopidogrel response variability in Spanish patients with stable coronary artery disease [31] . However, the relationship between CYP3A4*1G and clopidogrel resistance in Chinese patients with ischemic stroke had not been investigated previously.…”

Investigating the Mechanisms of Hyporesponse to Antiplatelet Approaches

“…29 Five different single nucleotide polymorphisms of CYP3A4 were examined in 82 patients receiving clopidogrel maintenance therapy who were at the steady-state phase (>1 month) of clopidogrel therapy. Carriers of the CYP3A4 polymorphism IVS10+12A allele had reduced GP IIb/IIIa receptor activation and increased responsiveness to clopidogrel (p = 0.025 and p = 0.02, respectively); clopidogrel-naïve patients with the IVS10+12A allele also had reduced GP IIb/IIIa activation during the 24 h following a loading dose (p = 0.025), increased platelet inhibition (p = 0.006), and better drug response (p = 0.003).…”

Clopidogrel Pharmacogenetics

“…Было показано, что активность цитохрома CYP3A4 коррелирует со степенью тормо-жения АДФ-индуцированной (20 мкмоль/л) агрега-цией тромбоцитов на фоне приема клопидогрела (r -0,6, p=0,003) [18]. D. J. Angiolillo и соавторы [19] показали влияние полиморфизма IVS10+12G/A гена CYP3A4 на степень торможения агрегации тромбоци-тов на фоне приема клопидогрела в группе из 82 па-циентов с ИБС. Исследовались степень активации гли-копротеиновых рецепторов GPIIb/IIIa тромбоцитов и агрегация тромбоцитов до и на фоне лечения клопи-догрелом.…”

“…Исследовались степень активации гли-копротеиновых рецепторов GPIIb/IIIa тромбоцитов и агрегация тромбоцитов до и на фоне лечения клопи-догрелом. На фоне лечения клопидогрелом у носите-лей IVS10+12A аллеля отмечались достоверно более низкие значения АДФ-индуцированной (2 мкмоль/л) степени активации GPIIb/IIIa рецепторов тромбоцитов (p=0,025) и агрегации тромбоцитов (17,4±10,9% про-тив 30,6±19,5%; p=0,035) [19].…”