Clopidogrel, a thienopyridine derivative, is a novel platelet antagonist that is several times more potent than ticlopidine but associated with fewer adverse effects. After repeated 75-mg oral doses of clopidogrel, plasma concentrations of the parent compound, which has no platelet-inhibiting effect, are very low. Clopidogrel is extensively metabolized in the liver. The main circulating metabolite is a carboxylic acid derivative with a plasma elimination half-life of 7.7 ± 2.3 hours. Approximately 50% of an oral dose is excreted in the urine and the remaining 50% in feces over the following 5 days. Dose-dependent inhibition of platelet aggregation is observed 2 hours after a single oral dose of clopidogrel, with a more significant inhibition achieved with loading doses (≥300 mg) by approximately 6 hours. Repeated doses of 75 mg of clopidogrel per day inhibit adenosine diphosphate (ADP)-mediated aggregation, with steady state being reached between day 3 and day 7. At steady state, the average inhibition to ADP is between 40% and 60%. Based on ex vivo studies, clopidogrel is approximately 100-fold more potent than ticlopidine. There are no cumulative antiplatelet effects with prolonged oral administration. The combined administration of clopidogrel (300 mg loading dose) and aspirin yields a readily discernible platelet-inhibiting effect within 90 to 120 minutes. Clopidogrel selectively inhibits the binding of ADP to its platelet receptor (P2Y12) and the subsequent G-protein–linked mobilization of intracellular calcium and activation of the glycoprotein (GP)IIb/IIIa complex (Gachet et al., 1992). The specific receptor has been cloned and is abundantly present on the platelet surface (Hollopter et al., 2001). Clopidogrel has no direct effect on cyclooxygenase, phosphodiesterase, or adenosine uptake. Clopidogrel is rapidly absorbed following oral administration with peak plasma levels of the predominant circulating metabolite occurring approximately 60 minutes later. Administration with meals does not significantly modify the bioavailability of clopidogrel. The available information suggests that clopidogrel offers safety advantages over ticlopidine, particularly with regard to bone marrow suppression and other hematologic abnormalities. Although thrombotic thrombocytopenic purpura (TTP) has been reported with clopidogrel (Bennett et al., 2000), its occurrence (11 cases per 3 million patients treated) is rare, and has not been reported in randomized clinical trials performed to date.
Plasma concentrations of 5-fluorouracil and F-β-alanine following oral administration of S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, as compared with protracted venous infusion of 5-fluorouracil