Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel

Abstract

Summary. Background: Thienopyridines are metabolized to active metabolites that irreversibly inhibit the platelet P2Y 12 adenosine diphosphate receptor. The pharmacodynamic response to clopidogrel is more variable than the response to prasugrel, but the reasons for variation in response to clopidogrel are not well characterized. Objective: To determine the relationship between genetic variation in cytochrome P450 (CYP) isoenzymes and the pharmacokinetic/pharmacodynamic response to prasugrel and clopidogrel. Methods: Genotyping was performed for CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP3A4 and CYP3A5 on samples from healthy subjects participating in studies evaluating pharmacokinetic and pharmacodynamic responses to prasugrel (60 mg, n = 71) or clopidogrel (300 mg, n = 74). Results: In subjects receiving clopidogrel, the presence of the CYP2C19*2 loss of function variant was significantly associated with lower exposure to clopidogrel active metabolite, as measured by the area under the concentration curve (AUC 0-24 ; P = 0.004) and maximal plasma concentration (C max ; P = 0.020), lower inhibition of platelet aggregation at 4 h (P = 0.003) and poor-responder status (P = 0.030). Similarly, CYP2C9 loss of function variants were significantly associated with lower AUC 0-24 (P = 0.043), lower C max (P = 0.006), lower IPA (P = 0.046) and poor-responder status (P = 0.024). For prasugrel, there was no relationship observed between CYP2C19 or CYP2C9 loss of function genotypes and exposure to the active metabolite of prasugrel or pharmacodynamic response. Conclusions: The common loss of function polymorphisms of CYP2C19 and CYP2C9 are associated with decreased exposure to the active metabolite of clopidogrel but not prasugrel. Decreased exposure to its active metabolite is associated with a diminished pharmacodynamic response to clopidogrel.

Pharmacokinetics and pharmacodynamics of single and multiple doses of prasugrel in healthy native Chinese subjects

“…The lower mean body weight of Asian subjects compared to Caucasian subjects may contribute to the higher exposure of prasugrel's active metabolite in Asians. Variations in CYP2C19 and CYP2C9 genetics cannot explain the higher active metabolite exposure in Asians because CYP2C19 and CYP2C9 genotypes associated with reduced function do not appear to affect the prasugrel PK or PD response [10] .…”

Clopidogrel Pharmacogenetics

“…Цитохром CYP2C9 также принимает уча-стие в метаболизме клопидогрела. Носительство ал-лелей CYP2C9*2 и CYP2C9*3 уменьшает Cmax на 47% (p=0,006), площадь под кривой AUC активного ме-таболита на 40% (p=0,043) и характеризуется на 37% меньшим снижением агрегации тромбоцитов через 4 часа от приема нагрузочной дозы клопидогрела 300 мг (p=0,046) по сравнению с аллелем "дикого" типа [16]. В работе A. Harmsze и сотр.…”

Cigarette smoking might weaken the prognostic significance of cytochrome P450 2C19*2 polymorphism in acute myocardial infarction patients

“…Clopidogrel is a prodrug, and requires multiple cytochrome (CYP) P450 isoenzymes for its activation, such as CYP1A2 and CYP2C19 11. Among these isoenzymes, the CYP2C19 is considered to be an extremely important enzyme in clopidogrel transformation 12.…”