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 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 SB 209670 infused at doses that ranged from 0.2 to 1.5 mirog 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 microg 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.


CONCLUSIONS
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.
Freed
M I
MI
SmithKline Beecham Clinical Pharmacology Unit, Presbyterian Medical Center of Philadelphia, University of Pennsylvania Health System, USA.
Wilson
D E
DE
Thompson
K A
KA
Harris
R Z
RZ
Ilson
B E
BE
Jorkasky
D K
DK
D000328:Adult; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D006801:Humans; D007189:Indans / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D012079:Renal Circulation / Q000187:drug effects*; D017596:Renal Plasma Flow, Effective / Q000187:drug effects; D016037:Single-Blind Method; D014655:Vascular Resistance / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007189:Indans; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-