Eeffets Of CYP2C19Genetic Polymorphism On The Pharmacokinettics And Pharmacodynamics Of Clopidogrel In Clinical Patients

Background:Clopidogrel is a kind of adenosine diphosphate receptor mediated by platelet aggregation inhibitors, can be used for the prevention of myocardial infarction, ischemic cerebral thrombosis obliterans, atherosclerosis and thrombosis embolism caused by complications in Percutaneous coronary interention (Percutaneous coronary intervention, PCI) after the application, can significantly reduce the incidence of stent thrombosis, as PCI has one of the important drug standard antiplatelet therapy after surgery.However, the use of clopidogrel in patients with long-term treatment will happen again in acute coronary syndrome,(acute coronary syndrome, ACS) or even life-threatening. By a large number of studies have shown that this is mediated with clopidogrel platelet aggregation inhibition rate (inhibition of platelet activation, IPA) caused by individual differences. In the conventional treatment, part of the use of Clopidogrel in patients after, cannot achieve the expected antiplatelet effect, this showed no response to Clopidogrel (Clopidogrel low response, CNR) or low response (Clopidogrel low responder, CLR) phenomenon referred to as Clopidogrel resistance (Clopidogrelresistance, CR). Clinical survey, about25%of the patients will appear the phenomenon of clopidogrel inadequate antiplatelet therapy, thus lead to increased ACS events again hair. Therefore, in recent years, the individual differences of clopidogrel response research by more and more attention.The clopidogrel has no anticoagulant effect as a prodrug itself, after the Cytochrome P450(CYP Cytochrome P450,) metabolism after converted to active metabolites, to produce platelet inhibition effect. Clopidogrel in the body of the function in the process, mainly by the metabolism of CYP2C19, are greatly influenced by CYP2C19gene polymorphisms, in which research is one of the hottest CYP2C19*2, CYP2C9*3mutant alleles and75%～85%of weak metabolism exists CYP2C19*2mutant alleles, the mutation is681g>A single nucleotide polymorphism, single nucleotide polymorphisms, SNPS), the incidence rate is as high as30%of people in Asia. CYP2C19*3variation for636g> ASNP, crowd incidence is relatively low in Asia, at5%. CYP2C19*2*3mutations can be ahead of time to suspend the transcription and protein amino acid212-bit code, will lead to generate any variant without the metabolic activity of the protein, produce weak metabolic phenotype. Given the weak metabolic phenotype of CYP2C19crowd incidence is higher in Asia, we have necessary to compare study of CYP2C19genetic polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel, help clinical individualized medication consultation.Objective:Study of CYP2C19genetic polymorphism distribution on pharmacokinetic and pharmacodynamic effects of clopidogrel, explore clopidogrel metabolism characteristics and mechanism of CR, individualized medication for clopidogrel to provide certain theoretical basis.Materials and methods:1. Subjects and tissue preparationWe collected50cases of clinical coronary heart disease patients, hospitalized in confirmation before no taking clopidogrel and clinical medication for the first time under the premise of75mg, respectively before (0h) and use2ml of blood collected after2h,8h, blood collection quickly after centrifugal separation and-20temperature cryopreservation processing, so that subsequent experiment.The study design was approved by the Committee on Human Research of Zhengzhou University.2. Observed indicatorsThe following indices were detected:(1) HPlC-MS-Ms method determination of clopidogrel in real-time blood drug concentration as a pharmacokinetic indicators;(2) application of a polymerase chain reaction restriction fragment length polymorphism (PCR RFLP) method to determine CYP2C19genotype, divided into strong metabolic group (homEM), metabolic type (hetEM) and weak in the metabolic model (PM)3groups, each group of people; Different blood sampling point (3) turbidimetric method, platelet aggregation rate as pharmacodynamic indexes in real-timeStatistical analysisThe analyses were performed by SPSS17.0statistical software. Data are presented as mean±SD. Correlation analyses were performed by Pearson correlation analysis. P values of less than0.05were taken as significant.Results:1. CYP2C19gene polymorphisms for pharmacokinetic effects of clopidogrel HP1C-MS-MS detection results show that metabolism of weak group (PM) of clopidogrel metabolism of blood drug concentration significantly greater than in the group and the strong metabolism,(p<0.01)2. CYP2C19gene polymorphisms for clopidogrel pharmacodynamics effectStrong, metabolic group, compared the weak metabolomic residual platelet activity (residual platelet reactivity, RPR) higher (P<0.02).Conclusions:CYP2C19gene polymorphisms could affect the pharmacokinetics and pharmacodynamics of clopidogrel, CYP2C19*2,*3loci mutation can make clopidogrel metabolism slows, platelet aggregation rate rise.