PHARMACOKINETICS AND PLATELET ANTIAGGREGATING EFFECTS OF BERAPROST, AN ORAL STABLE PROSTACYCLIN ANALOG, IN HEALTHY-VOLUNTEERS

Beraprost sodium (BPS) is an orally stable analogue of prostacyclin th at inhibits adenylate-cyclase-dependent platelet aggregation and is pr oposed for treatment of chronic arterial occlusion. To determine the d uration and intensity of platelet antiaggregation with BPS, 12 healthy , nonsmoking, male white volunteers participated in a double-blind, do se-escalating design with randomized placebo, placebo-controlled, cros s-over study. After overnight fasting, single (20, 40, 60 mug and plac ebo) and repeated [20, 40, 60 mug and placebo three times daily (t.i.d .) for 3 days] oral doses of BPS were administered. Mean percentage of inhibition of ADP-induced aggregation normalized to placebo was measu red for 8 h after drug administration and related to plasma concentrat ions (Cp) of the active enantiomer (APS 314d). BPS 40 and 60 mug decre ased platelet aggregation 1 h after single doses, and 0.5 h and 1 h af ter repeated doses. BPS 20 mug had no significant effect. APS 314d pha rmacokinetics was linear, and its terminal half-life (t1/2) ranged fro m 0.50 +/- 0.21 to 0.91 +/- 0.27 h (mean +/- SD) independently of BPS dose. Antiaggregating effects were poorly related to Cp of APS 314d (r 2 less-than-or-equal-to 0.2). Some subjects complained of moderate pos tdrug absorption headaches (7 of 12 after single and 8 of 12 after rep eated doses) and flushes (6 of 12 and 7 of 12, respectively). These da ta indicate that orally active prostacyclin BPS (40 or 60 mug) exerts its maximal antiaggregating effects between 0.5 and 1 h.