Pharmacology: Pharmacodynamics: Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Biotransformation of Clopidogrel is necessary to produce inhibition of platelet aggregation, but an active metabolite responsible for the activity of the drug has not been isolated. Clopidogrel also inhibits platelet aggregation induced by agonist other than ADP by blocking the amplification of platelet activation by released ADP. Clopidogrel does not inhibit phosphodiesterase activity. Clopidogrel acts by irreversibly modifying the platelet ADP receptor. Consequently, platelets exposed to Clopidogrel are affected for the remainder of their lifespan.
Dose dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of Clopidogrel. Repeated doses of 75 mg Clopidogrel per day inhibits ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between day 3 and day 7. At steady state, the average inhibition level observed with a dose of 75 mg Clopidogrel per 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: Clopidogrel is rapidly absorbed after oral administration of repeated doses of 75 mg Clopidogrel (base), with peak plasma levels (approx. 3 mg/mL) of the main circulating metabolite occurring approximately 1 hour after dosing. Clopidogrel is extensively metabolized by the liver. The main circulating metabolite is the carboxylic acid derivative and both the parent compound and the carboxylic acid derivative have no effect on platelet aggregation. Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). Following an oral dose of 1C-labeled Clopidogrel in humans, approximately 50% was excreted in the urine and approximately 46% in the feces in the 5 days after dosing. The elimination half-life of the main circulating metabolite was 8 hours after single and repeated administration. Administration of Clopidogrel with meals did not significantly modify the bioavailability of Clopidogrel as assessed by the pharmacokinetics of the main circulating metabolite.