Pharmacokinetics and pharmacodynamics of SE 209670, an endothelin receptor antagonist: Effects on the regulation of renal vascular tone

Objective: To evaluate the pharmacokinetics and pharmacodynamics of an infusion of SE 209670, a non peptide endothelin-A/endothelin-B receptor antagonist. Methods: The study was conducted in 2 parts. Part 1 was a placebo-controlled, single-blind, rising-dose crossover evaluation of the pharmacokinetics and safety of SE 209670 infused at doses that ranged from 0.2 to 1.5 mu g.kg(-1) for approximately 8 hours in 17 healthy male volunteers. In part 2, renal hemodynamic effects of a 4-hour infusion of SE 209670 were assessed in 10 healthy male volunteers in a 2-period, period-balanced, single-blind, randomized, placebo-controlled crossover study. Results: SE 209670 appeared to display Linear kinetics over the dose range from 0.2 to 1.5 mu g.kg(-1).min(-1). The half-life was approximately 4 to 5 hours. Plasma immunoreactive endothelin-l increased in an apparent dose-dependent manner, Mean renal hemodynamic responses (para-aminohippurate clearance) increased by approximately 15% relative to placebo (P = .007), Renal sodium excretion was similar during SE 209670 and placebo infusion. Conclusion: The pharmacokinetics of intravenous SE 209670 appeared to be linear, and infusion resulted in dose-related increases in immunoreactive endothelin-l, The lack of an ti-natriuretic effect and the renal vasodilator response observed in this study indicate that SE 209670 does not possess any partial agonist activity. Further, the renal hemodynamic response supported a potential physiologic role for endogenous endothelin in the maintenance of renal vascular tone in humans.