Prolonged pharmacodynamic effects of S-0139, an intravenously administered endothelin A (ET_A) antagonist, in the human forearm blood flow model

Aims: To estimate the pharmacologically active dose range of a new investigational compound S-0139, a selective endothelin A (ET_A) receptor antagonist, in man, and to examine the duration of its pharmacodynamic effect. Methods: Venous occlusion plethysmography was performed to assess changes in forearm blood flow following intra-brachial administration of endothelin-1 (ET-1). ET_A antagonists have been shown to block ET-1-induced vasoconstriction in this model. The study was conducted in three parts: (1) a pilot study to explore dose-response (dose range 0.08-13.33 μg kg^-1 min^-1), (2) a randomized study to confirm dose-response (placebo, 2.5, 6.67 and 15 μg kg^-1 min ^-1), and (3) a delayed administration study (15.7 μg kg ^-1 min^-1) to explore the duration of the pharmacodynamic effect. In all studies a 3-h infusion of S-0139 was given and during the last 90 min of the infusion, ET-1 was infused concurrently for 90 min. In study (3) a second ET-1 infusion was given starting 3 h after completion of the first. Results: Intravenously administered S-0139 resulted in significant inhibition of ET-1-induced vasoconstriction in the forearm (plasma concentration 800-2000 ng ml^-1). In the delayed administration study, the same extent of inhibition was still present when ET-1 was administered 3 h after the end of infusion of S-0139, even though the S-0139 plasma concentrations (mean 17 ng ml^-1) were well below pharmacologically active concentrations as determined in studies 1 and 2. Conclusions: S-0139 dose-dependently blocks ET-1-mediated vasoconstriction in the forearm and has a prolonged duration of effect beyond that expected from its pharmacokinetic profile.