Clopidogrel - How It Works
Clinical pharmacology details from the US FDA-approved label: how Clopidogrel works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets.
12.2 Pharmacodynamics 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 P2Y 12 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 to 10 days).
Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.
Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of clopidogrel tablets.
Repeated doses of 75 mg clopidogrel tablets 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 tablets 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.
Geriatric Patients Elderly (≥75 years) and young healthy subjects had similar effects on platelet aggregation.
Renally Impaired Patients After repeated doses of 75 mg clopidogrel tablets per day, patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) and moderate renal impairment (creatinine clearance from 30 to 60 mL/min) showed low (25%) inhibition of ADP-induced platelet aggregation.
Hepatically Impaired Patients After repeated doses of 75 mg clopidogrel tablets per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects.
Gender In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women.
12.3 Pharmacokinetics Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites.
Absorption After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed.
Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.
Effect of food Clopidogrel tablets can be administered with or without food.
In a study in healthy male subjects when clopidogrel tablets 75 mg per day was given with a standard breakfast, mean inhibition of ADP-induced platelet aggregation was reduced by less than 9%.
The active metabolite AUC 0-24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite C max .
Pharmacokinetics
12.3 Pharmacokinetics Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites. Absorption After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites. Effect of food Clopidogrel tablets can be administered with or without food. In a study in healthy male subjects when clopidogrel tablets 75 mg per day was given with a standard breakfast, mean inhibition of ADP-induced platelet aggregation was reduced by less than 9%. The active metabolite AUC 0-24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite C max . Similar results were observed when a clopidogrel tablets 300 mg loading dose was administered with a high-fat breakfast. Metabolism Clopidogrel is extensively metabolized by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450 enzymes. 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. The active metabolite is formed mostly by CYP2C19 with contributions from several other CYP enzymes, including CYP1A2, CYP2B6 and CYP3A. The active thiol metabo