Sign Out
Mechanism of Action: Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible. Consequently, platelets exposed to clopidogrel's active metabolite are affected for the remainder of their lifespan (about 7-10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.
Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or subject to inhibition by other drugs, not all patients will have adequate platelet inhibition.
Dose-dependent inhibition of platelet aggregation can be seen 2 hrs after single oral doses of clopidogrel. Repeated doses of clopidogrel 75 mg/day inhibit ADP-induced platelet aggregation on the 1st day, and inhibition reaches steady state between day 3 and day 7. At steady state, the average inhibition level observed with a dose of clopidogrel 75 mg/day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.
Pharmacokinetics: Absorption: After single and repeated oral doses of 75 mg/day, clopidogrel is rapidly absorbed. Mean peak plasma levels of unchanged clopidogrel (approximately 2.2-2.5 ng/mL after a single 75-mg oral dose) occurred approximately 45 min after dosing. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.
Effect of Food: The effect of food on the bioavailability of the parent compound or active metabolite is currently not known.
Distribution: Clopidogrel and the main circulating inactive metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The binding is nonsaturable in vitro up to a concentration of 100 mcg/mL.
Metabolism: Clopidogrel is extensively metabolized by the liver. In vitro and in vivo, clopidogrel is metabolized according to 2 main metabolic pathways: One mediated by esterases and leading to hydrolysis into its inactive carboxylic acid derivative (85% of circulating metabolites), and one mediated by multiple cytochromes P450. Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. In vitro, this metabolic pathway is mediated by CYP3A4, CYP2C19, CYP1A2 and CYP2B6. The active thiol metabolite, which has been isolated in vitro, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation.
Elimination: Following an oral dose of 14C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post-dosing. After a single, oral dose of 75 mg, clopidogrel has a t½ of approximately 6 hrs. The elimination half-life of the inactive acid metabolite was 8 hrs after single and repeated administration. Covalent binding to platelets accounted for 2% of radiolabel with a half-life of 11 days. In plasma and urine, the glucuronide of the carboxylic acid derivative is also observed.
Pharmacogenetics: Several polymorphic CYP450 enzymes activate clopidogrel. CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype. The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and CYP2C19*3 alleles correspond to reduced metabolism.
The CYP2C19*2 and CYP2C19*3 alleles account for 85% of reduced function alleles in whites and 99% in Asians. Other alleles associated with reduced metabolism include CYP2C19*4, *5, *6, *7, and *8, but these are less frequent in the general population. Published frequencies for the common CYP2C19 phenotypes and genotypes are listed in the table as follows.
Click on icon to see table/diagram/imagePharmacogenetic testing can identify genotypes associated with variability in CYP2C19 activity.
There may be genetic variants of other CYP450 enzymes with effects on the ability to form clopidogrel's active metabolite.
Special Populations: The pharmacokinetics of clopidogrel's active metabolite is not known in these special populations.
Geriatric Patients: In elderly (≥75 years) volunteers compared to young healthy volunteers, there were no differences in platelet aggregation and bleeding time. No dosage adjustment is needed for the elderly.
Renally-Impaired Patients: After repeated doses of clopidogrel 75 mg/day in patients with severe renal impairment (creatinine clearance from 5-15 mL/min), inhibition of ADP-induced platelet aggregation was lower (<25%) than that observed in healthy volunteers, however, the prolongation of bleeding time was similar to healthy volunteers receiving clopidogrel 75 mg/day.
Hepatically-Impaired Patients: After repeated doses of clopidogrel 75 mg/day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects. The mean bleeding time prolongation was also similar in the 2 groups.
Gender: The incidence of clinical outcome events, other adverse clinical events, and abnormal clinical laboratory parameters was similar in men and women.
Race: The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism differs according to race/ethnicity.
