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

Objective To evaluate the pharmacokinetics and pharmacodynamics of an infusion of SB 209670, a nonpeptide 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 SB 209670 infused at doses that ranged from 0.2 to 1.5 μg · kg]−1 for approximately 8 hours in 17 healthy male volunteers. In part 2, renal hemodynamic effects of a 4‐hour infusion of SB 209670 were assessed in 10 healthy male volunteers in a 2‐period, period‐balanced, single‐blind, randomized, placebo‐controlled crossover study. Results SB 209670 appeared to display linear kinetics over the dose range from 0.2 to 1.5 μg · kg−1 · min−1. The half‐life was approximately 4 to 5 hours. Plasma immunoreactive endothelin‐1 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 SB 209670 and placebo infusion. Conclusion The pharmacokinetics of intravenous SB 209670 appeared to be linear, and infusion resulted in dose‐related increases in immunoreactive endothelin‐1. The lack of anti‐natriuretic effect and the renal vasodilator response observed in this study indicate that SB 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. Clinical Pharmacology & Therapeutics (1999) 65, 473–482; doi: