The inhibition of platelet aggregation by clopidogrel, a novel platelet ADP-receptor antagonist, was evaluated in healthy male volunteers in two single-dose studies. In one study, 10 subjects received, in increasing order, single doses of 100, 200, 400 and 600 mg of clopidogrel or placebo in five study periods, according to a randomized, doubleblind, protocol design. In the second study, 12 subjects received a single 400 mg dose of clopidogrel as capsules and as tablets, according to an open-label, randomized, crossover design. The interval between the two administrations was seven days. Platelet aggregation induced by ADP (2, 5 and 10 microM) and by collagen (0.5 and 1 microg/mL; rising-dose study only) was assessed from blood samples collected over a period of 24 hours to 72 hours postdose. The inhibition of platelet aggregation was expressed as the mean percent change from baseline in maximum platelet aggregation. The effect of clopidogrel on bleeding time was also assessed. Clopidogrel induced a statistically significant inhibition of ADP-induced platelet aggregation at all doses. With 5 microM of ADP, the inhibition was dose-related up to a dose of 400 mg, with no further increase at a dose of 600 mg. At 2 hours, mean inhibition ranged from 12+/-6% (100 mg) to 42 +/-6% (400 mg), and at 24 hours, it ranged from 17+/-7% (100 mg) to 43+/-9% (400 mg). After 400 mg, the inhibition of platelet aggregation remained stable from 2 hours up to 72 hours, with mean percentages of inhibition ranging from 49 to 39%. Clopidogrel only showed a slight-to-moderate inhibitory effect on collagen-induced platelet aggregation. A mean bleeding time prolongation of 1.7 was observed 5 hours after the 400 mg and 600 mg doses; it was statistically significant only following the higher dose. Individual bleeding time prolongations ranged from 1 to 2.85. Clopidogrel was well tolerated at all doses. The results of these studies were part of the rational for the choice of the loading dose.