Take 75mg orally once or several times a day, and clopidogrel absorbs quickly. The average plasma concentration of clopidogrel of the prototype compound reached its peak at about 45 minutes after administration (about 2.2-2.5ng/ml after a single oral administration of 75mg). According to the excretion of clopidogrel metabolites in urine, at least 50% drugs are absorbed. In vitro distribution tests showed that clopidogrel and its main circulating metabolites (inactive) reversibly bound to human plasma protein (98% and 94% respectively) and were unsaturated in a large concentration range. The metabolism of clopidogrel is mainly through the liver. The metabolism of clopidogrel in vivo and in vitro goes through two main metabolic pathways: one pathway is mediated by esterase, and it is metabolized into inactive acid derivatives (85% circulating metabolites) through hydrolysis, and the other pathway is mediated by cytochrome P450. Clopidogrel is firstly metabolized into 2- oxygen-clopidogrel intermediate metabolite. Then the 2- oxygen-clopidogrel intermediate metabolite is metabolized to form an active metabolite, namely clopidogrel thiol derivatives. In vitro, this metabolic pathway is mediated by CYP3A4, CYP2C 19, CYP 1A2 and CYP2B6. Active thiol derivatives classified in vitro bind to platelet receptors rapidly and irreversibly, thus inhibiting platelet aggregation. Cmax of active metabolites after a single loading dose of 300mg clopidogrel was twice as high as that after 4 days of 75mg maintenance dose. Cmax appears about 30 to 60 minutes after administration. After excluding clopidogrel labeled with [sup] 14[/sup]C, about 50% was excreted in urine and 46% in feces within 120 hours. After a single oral administration of 75mg clopidogrel, the half-life of clopidogrel is 6 hours, and the half-life of active metabolites is about 30 minutes. After single and repeated administration, the elimination half-life of the main metabolites (inactive) in circulation is 8 hours. Genetic pharmacology CYP2C 19 is involved in the formation of active metabolite and intermediate metabolite 2- oxo-clopidogrel. The pharmacokinetics and antiplatelet effect of active metabolites of clopidogrel (the latter was determined by platelet aggregation rate in vitro) were different from those of CYP2C 19 genotype. The CYP2C 19* 1 allele corresponds to a complete functional metabolism pattern, while the CYP2C 19*2 and CYP2C 19*3 alleles are functionally absent. The CYP2C 19*2 and CYP2C 19*3 alleles account for 85% of the chronic metabolic alleles in whites and 99% in Asians. Other patients with slow metabolism carry two functional deletion alleles as mentioned above. The reported frequencies of CYP2C 19 slow metabolism genotypes are about 2% in whites, 4% in blacks and 14% in China. There are methods to detect the CYP2C 19 genotype of patients. In the crossover experiment among 40 healthy subjects, * * * set up four groups of CYP2C 19 metabolic subjects (ultra-fast metabolism, fast metabolism, intermediate metabolism and slow metabolism), and each group included 10 subjects to evaluate the pharmacokinetic characteristics and antiplatelet function of each group. The administration scheme is as follows: the first dose is 300 mg, and then 70 mg. The first dose is 600 mg, and then 150 mg/day; The administration time of both regimens is 5 days (steady state). There was no significant difference in plasma concentration and average platelet aggregation inhibition rate (IPA) data of active metabolites of clopidogrel between ultra-fast, fast and intermediate metabolic subjects. The plasma concentration of slow metabolizers is 63-7 1% lower than that of fast metabolizers. After administration of 300mg/75mg, the antiplatelet effect of slow metabolizers was weakened, and the average IPA(5μMADP) was 24% (24h) and 37% (5th day), while that of fast metabolizers was 39% (24h) and 58% (5th day), and that of intermediate metabolizers was 37% (24h). The plasma concentration of active metabolites in chronic metabolic patients receiving 600mg/ 150mg dose regimen is higher than that of 300mg/75mg dose regimen. In addition, the IPA of subjects receiving 600mg/ 150mg dosage regimen was 32%(24 hours) and 6 1% (day 5), which was higher than that of subjects with slow metabolism receiving 300mg/75mg dosage regimen. The plasma concentration and IPA value of chronic metabolic subjects receiving 600mg/ 150mg of active metabolites can reach the level of other metabolic subjects receiving 300mg/75mg. At present, there is a lack of clinical end-point research to help patients with slow metabolism determine the appropriate dose and dosage regimen. A meta-analysis of 335 patients treated with clopidogrel in six projects showed similar results: compared with fast metabolizers, the exposure of active metabolites in middle metabolizers decreased by 28% and that in slow metabolizers decreased by 72%; At the same time, platelet aggregation inhibition (5μm ADP) also decreased, and the difference distribution between IPA and fast metabolizers was 5.9% and 2 1.4%. There is still a lack of prospective, randomized and controlled trial results to evaluate the influence of CYPC 19 genotype on the clinical outcome of patients receiving clopidogrel treatment. However, there are some retrospective analysis results to evaluate the changes of clinical outcomes of patients with different genotypes after clopidogrel treatment: cure (n=272 1), charm (n=2428), clear -TIMI 28(n=227) and triton -TIMI 38(n= 1477). There are also some published cohort studies. In TRITON-TIMI 38 and three cohort studies (Collet, Sibbing, Giusti), it was observed that the incidence of cardiovascular events (death, myocardial infarction and stroke) or stent thrombosis was higher than that of patients with moderate metabolism and slow metabolism. In CHARISMA and a cohort study (Simon), only patients with slow metabolism have a higher incidence of events than patients with fast metabolism. In CURE, CLARITY, ACTIVE-A and Trenk studies, no increase in cardiovascular events was observed in patients with different CYP2C 19 metabolic types. The number of subjects in these analyses may not be enough to detect the difference of clinical endpoint in patients with slow metabolism. The pharmacokinetics of active metabolites of clopidogrel in special population is not clear. Renal function damage: The inhibition of ADP-induced platelet aggregation (25%) in patients with severe renal damage (creatinine clearance rate 5- 15ml/min) after repeated administration of clopidogrel 75mg daily 1 time was lower than that in healthy volunteers, but the bleeding time was the same as that in healthy volunteers taking clopidogrel 75mg daily. Moreover, all patients have good clinical tolerance. Liver function damage: In patients with severe liver function damage, the inhibitory effect of clopidogrel on ADP-induced platelet aggregation after oral administration of 75mg 10 a day is similar to that observed in healthy subjects. The average bleeding time of the two groups was similar. Race: The genotypes of CYP2C 19 intermediate metabolism and slow metabolism vary according to race/nationality (see Genetics and Pharmacology). According to the existing literature reports, there are limited data available for evaluating the clinical significance of CYP2C 19 genotype in Asian population.