Norplat/Norplat-S Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action: Clopidogrel is an inhibitor of platelet aggregation ie, a drug that inhibits the ability of platelets to clump together as part of a blood clot.
Clopidogrel appears to act by blocking the adenosine phosphate (ADP) receptor, which prevents fibrinogen-binding to the receptor. This decreases the ability of platelet adhesion and aggregation. Clopidogrel is a prodrug and requires biotransformation to produce inhibition of platelet aggregation.
Norplat: The active metabolite of clopidogrel also inhibits platelet aggregation induced by agonists other than ADP by blocking the amplification of platelet activation by released ADP.
Norplat-S: Aspirin: Acetylsalicylic acid inhibits the activity of the enzyme cyclooxygenase and thus, prostaglandins and thromboxane formation are decreased. By blocking thromboxane synthesis, acetylsalicylic acid inhibits rapidly the platelet aggregation, this action is irreversible. Acetylsalicylic acid may also inhibit formation of prostacyclin, a platelet aggregation inhibitor, this action is reversible.
Pharmacokinetics: Norplat: Clopidogrel, after administration, requires hepatic biotransformation to an active metabolite. Hepatic activation is thought to be mediated by the CYP P-450 1A subfamily. The uncharacterized active metabolite is labile and highly reactive.
Absorption: Following oral administration, clopidogrel is rapidly absorbed. Absorption is at least 50% and is not significantly affected by food. Peak plasma concentrations (roughly 3 mg/L) of the primary circulating metabolite occur at about 1 hr following multiple dosing of 75 mg/day. Plasma concentrations of the parent drug are undetectable 2 hrs after an oral dose.
Distribution: Clopidogrel and the main circulating metabolite bind reversibly to human plasma proteins (98% and 94%, respectively).
Metabolism: Clopidogrel is extensively metabolized in the liver. The main circulating metabolite is the carboxylic acid derivative, and it has no effect on platelet aggregation. The active metabolite appears to be thiol derivative but not has been identified in the plasma.
Elimination: Clopidogrel and its metabolites are excreted about equally in urine and feces. The t_½ of the carboxylic acid derivative is about 8 hrs.
Norplat-S: Clopidogrel is rapidly absorbed after oral administration. Absorption is at least 50%. It is a prodrug and is extensively metabolized in the liver, mainly to the inactive carboxylic acid derivative. The active metabolite appears to be a thiol derivative but has not been identified in plasma. Clopidogrel and the carboxylic acid derivatives are highly protein bound. Clopidogrel and its metabolites are excreted in the urine and feces. After oral administration, about 50% of a dose is recovered from the urine and 46% from the feces.
Aspirin: After oral doses, absorption of non-ionized aspirin occurs in the stomach and intestine. Some aspirin is hydrolyzed to salicylate in the gut wall. Once absorbed, aspirin is rapidly converted to salicylate but during the first 20 min after an oral dose, aspirin is the predominant form of the drug in the plasma. Aspirin is 80-90% bound to plasma proteins and is widely distributed; its volume of distribution is reported to be 170 mL/kg in adults. As plasma-drug concentrations increase, the binding sites on the proteins become saturated and the volume of distribution increases. Both aspirin and salicylate have pharmacological activity although only aspirin has an antiplatelet effect. Salicylate is extensively bound to plasma proteins and is rapidly distributed to all body parts. Salicylate appears in breast milk and crosses placenta, and is mainly eliminated by hepatic metabolism.
Salicylate is also excreted unchanged in the urine, the amount excreted by this route increase with increasing dose and also depends on urinary pH, about 30% of a dose being excreted in alkaline urine compared with 2% of a dose in acidic urine. Renal excretion involves glomerular filtration, active renal tubular secretion and passive tubular reabsorption.
Special Populations: Norplat/Norplat-S: Renal Insufficiency: After repeated doses of clopidogrel 75 mg/day plasma levels of the main circulating metabolite were lower in plasma impairment (CrCl from 5-15 mL/min) compared to subjects with moderate renal impairment (CrCl of 30-60 mL/min) or healthy subjects. However, the prolongation of bleeding time was similar. No dose adjustment is required in mild to moderate renal impairment patients.