Research On The Effects Of Genetic Polymorphism And Plasm Concentration Of Clopidogrel On Individual Response Variability And Clinical Events

Objective:To study the ABCB1, CYP2C19gene polymorphisms for acute coronary syndrome in patients with PCI postoperative curative effect and determine the plasm concentration of clopidogrel and its metabolites, which provides more clinical basis for guiding individualized antiplatelet therapy and observable indicators.Methods:300patients with coronary heart disease undergoing PCI were enrolled, including234male patients and66female patients. According to monitoring the Thrombelastograph, Adenosine diphosphate pathway inhibition rate＞80%for clopidogrel remarkable efficacy group,105cases (group A); ADP inhibition rate of50%～80%for clopidogrel effective group100cases (group C); ADP inhibition rate<50%for clopidogrel poor responsiveness group95cases (group B). All of the patients were performed by PCR combined with restrictive fragment length polymorphism (PCR-RELP) method detecting CYP2C19and ABCB1genetic polymorphisms; Of200patients were divided into two groups, including ADP inhibition rate＞80%for clopidogrel excellent responsiveness(group E,N=105)and＜50%for clopidogrel low responsiveness(group F,N=95). These patients were performed by high performance liquid chromatography with electrospray tandem mass spectrum methods (HTLC-MS/MS), which was applied for dertermining the plasm concentration level of clopidogrel metabolites. We also analyzed the differences between ACS patients with clopidogrel responsiveneses in gene polymorphism and the concentration level of clopidogrel metabolites.Results:1.Clopidogrel poor responsiveness group in gender and smoking history difference was statistically significant between other two groups (P<0.05), among poor responsiveness group patients with no history of smoking were more, and women are more likely to happen clopidogrel poor responsiveness trends; there was no difference of clinical data among three groups (p>0.05).2. There was no significant difference in each group with ABCB1gene polymorphism, but the rate of patients with CC genotype in poor responsiveness group was61%(58/95);according to monitoring the CYP2C19genotype,there were28poor metabolizers (9.3%),157intermediate metabolizers(52.3%) and115extensive metabolizers (38.3%), and the ratio of patients with poor metabolizers in clopidogrel poor responsiveness group was significantly higher than that of other two groups, difference between groups was statistically significant(p<0.05).3. There is obvious difference in the incidence of recurrent angina pectoris and bleeding events between poor responsiveness group and other two groups (p<0.05); there is no obvious difference among patients with ABCB1genotype, however among patients with CYP2C19poor metabolizer genotype (CYP2C19*1/*2or*1/*3) the rate of clinical events was higher than that of patients with extensive metabolizer genotype, there was statistical difference between two groups (p<0.05). No difference between the impact on clinical events among ABCB1and CYP2C19gene combination.4. Determining the concentration of clopidogrel metabolites between clopidogrel excellent responsiveness group and low responsiveness group, results show that plasma concentration of clopidogrel in low responsiveness group was lower than that in excellent responsiveness group,and relative concentration of acid metabolites was higher than in excellent responsiveness group (all P<0.05); Two groups in plasm relative concentration of2-oxo-clopidogrel had no statistical significance.5. Clopidogrel concentration among patients with ABCB1TT genotype in clopidogrel low responsiveness group was lower than that in excellent responsiveness group; relative concentration of2-oxo-clopidogrel and carboxylic acid metabolites among patients with CT genotype in low responsiveness group was higher than that of excellent responsiveness group; CYP2C19*2or*3in any patients with metabolic genes, clopidogrel concentration in low responsiveness group was lower than that in excellent responsiveness group, the difference was statistically significant (all p<0.05).6. Carrying ABCB1TT homozygous and CYP2C19*2or*3any metabolic genes of patients, the concentration of clopidogrel in low responsiveness group was lower than that in excellent responsiveness group; Among patients with CT heterozygous or CC homozygous and CYP2C19intermediate metabolizer (CYP2C19*1/*2or*1/*3) gene, relative concentration of2-oxo-clopidogrel is slightly lower than that in low responsiveness group, difference in each group was statistically significant(p<0.05).7.There was no significant difference in ABCB1and CYP2C19gene combination on ADP inhibition rate.Conclusion:l.The ABCB1and CYP2C19gene polymorphisms influence in vivo pharmacokinetics and pharmacodynamics of clopidogrel, clopidogrel concentration in patients carrying the ABCB1gene mutation TT homozygous is significantly lower, and CYP2C19gene polymorphism affects clopidogrel metabolism in the body. The effect of clopidogrel metabolism among ABCB1and CYP2C19gene combination is more obvious,and no statistical difference between clopidogrel responsiveness and clinical events.2.The concentration level of clopidogrel metabolites influences clopidogrel ndividual responsiveness, and clopidogrel resistance or clopidogrel poor responsiveness may increase the risk of clinical cardiovascular events.