Clopidogrel + Aspirin

Clopidogrel is a prodrug. Its active metabolite binds irreversibly to the P2Y12 class of ADP receptors on platelets, and this stops platelets from being activated and clumping together. Inhibition of platelet aggregation depends on the dose and can be seen 2 hours after single oral doses. With repeated doses of 75 mg per day, ADP-induced platelet aggregation is inhibited from the first day, and inhibition reaches steady state between Day 3 and Day 7. Aspirin works by irreversibly inhibiting platelet cyclooxygenase. That stops the generation of thromboxane A2, a powerful inducer of platelet aggregation and vasoconstriction.

Pharmacokinetics

After repeated 75-mg oral doses of Clopidogrel (base), plasma concentrations of the parent compound are very low, and it has no platelet inhibiting effect. Beyond 2 hours after dosing, they are generally below the quantification limit (0.00025 mg/L). Clopidogrel is extensively metabolized by the liver. Its main circulating metabolite is the carboxylic acid derivative, which has no effect on platelet aggregation. This metabolite makes up about 85% of the circulating drug-related compounds in plasma. After an oral dose of 14C-labeled Clopidogrel in humans, about 50% is excreted in the urine and about 46% in the faeces over the next 5 days. Elimination half-life of the main circulating metabolite is 8 hours after single and repeated administration. Taking Clopidogrel with meals did not significantly change its bioavailability, as assessed by the pharmacokinetics of the main circulating metabolite.

Absorption and Distribution

Clopidogrel is rapidly absorbed after oral administration of repeated doses of 75 mg Clopidogrel (base), and peak plasma levels (3 mg/L) of the main circulating metabolite occur about 1 hour after dosing. Pharmacokinetics of this metabolite are linear in the dose range of 50 to 150 mg of Clopidogrel (plasma concentrations increase in proportion to dose). Based on urinary excretion of Clopidogrel-related metabolites, absorption is at least 50%. In vitro, Clopidogrel and the main circulating metabolite bind reversibly to human plasma proteins (98% and 94%, respectively). This binding is nonsaturable in vitro up to a concentration of 100 g/mL.

Metabolism and Elimination

In vitro and in vivo, Clopidogrel undergoes rapid hydrolysis into its carboxylic acid derivative. The glucuronide of the carboxylic acid derivative is also seen in plasma and urine.