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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 agonists 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 inhibit 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 but incompletely absorbed after oral administration, absorption appears to be at least 50%. It is aprodrug and is extensively metabolised in the liver, mainly to the inactive carboxylic acid derivative. The oxidative step isregulated primarily by Cytochrome P450 isoenzymes 2B6, 3A4, 1A1, 1A2 and 2C19. The active metabolite appears to be athiol derivative but has not been identified in plasma. Clopidogrel and the carboxylic acid derivative are highly plasmaprotein bound. Clopidogrel and its metabolites are excreted in urine and in faeces, after oral administration, about 50% of adose is recovered from the urine and about 46% from the faeces.
