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Pharmacological properties

Pharmacodynamics

Mechanism of action. Clopidogrel is a prodrug, one of its metabolites is an inhibitor of platelet aggregation. For the formation of an active metabolite that inhibits platelet aggregation, clopidogrel metabolism must be carried out using CYP 450 cytochrome enzymes. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to the P2Y12 receptor on the platelet surface and subsequent activation of the glycoprotein II complex IIIboprot due to which platelet aggregation is suppressed. Due to the irreversible nature of the binding, platelets that interact with clopidogrel remain under its action throughout their lives (about 7–10 days), normal platelet function is restored at a rate corresponding to the platelet renewal rate. Platelet aggregation, which is caused by agonists other than ADP, is also inhibited by blocking the amplification of platelet activation by ADP, which is released.

Since the active metabolite is formed using the enzymes of the CYP 450 cytochrome system, and some of them are polymorphic or are suppressed by other drugs, not all patients have a corresponding platelet suppression.

Pharmacodynamic effects. Repeated use of clopidogrel at a dose of 75 mg / day significantly suppressed ADP-induced platelet aggregation from the first day of use; such an effect gradually increased and reached a constant level with reaching an equilibrium state on the 3rd – 7th day. In equilibrium, the average level of platelet inhibition was observed against a background of a dose of 75 mg / day and ranged from 40-60%. Platelet aggregation and bleeding time gradually returned to baseline levels over an average of 5 days.

Acetylsalicylic acid inhibits platelet aggregation by irreversibly inhibiting cyclooxygenase prostaglandins and thus inhibits the formation of thromboxane A2, which causes platelet aggregation and vasoconstriction. This effect lasts throughout the life of the platelets.

Pharmacokinetics

Clopidogrel.

Suction. After a single and repeated oral administration at a dose of 75 mg / day, clopidogrel is rapidly absorbed. Cmax clopidogrel unchanged in blood plasma (approximately 2.2–2.5 ng / ml after a single oral dose of 75 mg) is achieved 45 minutes after administration. Absorption is at least 50% according to the number of clopidogrel metabolites excreted in the urine.

Distribution. In vitro, clopidogrel and the main circulating (inactive) metabolite reversibly bind to human plasma proteins (98 and 94%, respectively). The bond is unsaturated in vitro in a wide range of concentrations.

Metabolism. Clopidogrel is actively metabolized in the liver. In vitro and in vivo clopidogrel metabolism occurs in 2 main metabolic ways: one using esterase followed by hydrolysis to an inactive metabolite, which is a derivative of carboxylic acid (85% of circulating metabolites), the other through various P450 cytochromes. First, during the metabolism of clopidogrel, an intermediate metabolite 2-oxo-clopidogrel is formed. As a result of further metabolism of the intermediate metabolite of 2-oxo-clopidogrel, an active metabolite, a thiol derivative of clopidogrel, is formed. In vitro, this metabolic pathway is mediated by the isoenzymes of CYP 3A4, 2C19, CYP 1A2 and CYP 2B6. The active thiol metabolite, which was isolated in vitro, rapidly and irreversibly binds to platelet receptors, thus inhibiting platelet aggregation.

After a single dose of clopidogrel at a loading dose of 300 mg, indicator Cmax the active metabolite is twice as high as after taking the drug in a maintenance dose of 75 mg for 4 days. Cmax achieved after about 30-60 minutes after taking the drug.

Breeding.Within 120 hours after a person has taken 14C-labeled clopidogrel, about 50% was excreted in the urine and approximately 46% was excreted in the feces. After a single dose of 75 mg orally, T½ is about 6 hours. T½ the main circulating (inactive) metabolite was 8 hours after a single or repeated administration.

Pharmacogenetics. Clopidogrel activates several polymorphic P450 isoenzymes. CYP 2C19 is involved in the formation of both an active metabolite and an intermediate metabolite of 2-oxo-clopidogrel. According to ex vivo platelet aggregation quantification, the pharmacokinetic parameters and antithrombotic effect of the active metabolite of clopidogrel differ according to the CYP 2C19 genotype. The CYP 2C19 * 1 allele corresponds to a fully functional metabolism, while the alleles of CYP 2C19 * 2 and CYP 2C19 * 3 correspond to a reduced metabolism. As for the alleles, CYP 2C19 * 2 and CYP 2C19 * 3 include 85% of the alleles of reduced function in the inhabitants of the Caucasus and 99% in natives of Asia. Other alleles associated with decreased metabolism include CYP 2C19 * 4, * 5, * 6, * 7 and * 8, but they are less common in the general population. Information on the prevalence of phenotypes and genotypes of CYP 2C19, which are common, according to published data, is shown in the table below.

Table. The prevalence of phenotypes and genotypes of CYP 2C19

  Prevalence(%)
Metabolism Residents of the Caucasus (n = 1356) Representatives of the Negroid race (n = 966) Chinese (n = 573)
Extensive metabolism: CYP 2C19 * 1 / * 1 74 66 38
Intermediate metabolism: CYP 2C19 * 1 / * 2 or * 1 / * 3 26 29 50
Decreased metabolism: CYP 2С19 * 2 / * 2, * 2 / * 3 abo * 3 / * 3 2 4 14

To date, the effect of the CYP 2C19 genotype on the pharmacokinetics of the active metabolite of clopidogrel has been studied with 277 patients in 7 published studies. Decreased CYP 2C19-mediated metabolism in patients with a moderate or pronounced decrease in metabolism resulted in a decrease in Cmax and AUC of the active metabolite by 30-50% after loading doses of 300 mg or 600 mg and a maintenance dose of 75 mg. The decreased activity of the active metabolite leads to a weaker suppression of platelets or to a greater residual platelet reactivity. In a 21 published study involving 4520 patients, a reduced antiplatelet reaction to clopidogrel was noted in patients with a moderate or pronounced decrease in metabolism. The relative difference in the antiplatelet reaction to the effect of the drug between the groups distributed by genotype varied in different studies depending on the method that was used to evaluate the reaction, but usually exceeded 30%.

The relationship between the CYP 2C19 genotype and the result of clopidogrel administration was determined using 2 secondary analyzes of clinical trial data (CLARITY [n = 465] and TRITON-TIMI 38 [n = 1477] sub-studies) and 5 cohort studies (total n = 6489). In the CLARITY study and one of the cohort studies (n = 765; Trenk), the number of cardiovascular diseases did not depend much on the genotype. In the TRITON-TIMI study 38 and 3 cohort studies (n = 3516; Collet, Sibbing, Giusti) among patients with metabolic status impairment (combined moderate and severe) the number of cardiovascular diseases (myocardial infarction, stroke, including fatal ) or cases of stent thrombosis were more than in patients with extensive metabolism.

Conducting pharmacogenetic tests can help determine the genotypes on which the variability of CYP 2C19 activity depends.

Genetic variants of other CYP 450 isoenzymes may exist that affect the ability to form the active metabolite of clopidogrel.

There are no data on the pharmacokinetic parameters of the active metabolite of clopidogrel in these groups of patients.

Renal failure. After repeated administration of clopidogrel at a dose of 75 mg / day in patients with severe renal disease (creatinine clearance of 5-15 ml / min), inhibition of ADP-induced platelet aggregation was less (25%) than in healthy volunteers, however, the bleeding time was longer similar to the bleeding time observed in healthy volunteers who took 75 mg of clopidogrel per day. In addition, clinical tolerance was satisfactory in all patients.

Liver failure.After repeated administration of clopidogrel at a dose of 75 mg for 10 days in patients with severe hepatic insufficiency, the suppression of ADP-induced platelet aggregation was similar to that observed in healthy volunteers. The average increase in bleeding time in the 2 groups was also similar.

Racial affiliation. The predominance of CYP 2C19 alleles, which are

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