Characterization of the renal effects and renal elimination of sulotroban in the dog.
The renal effects and renal handling of the nonprostanoid thromboxane receptor antagonist, sulotroban (4-[2-(phenylsulfonylamino)ethyl]phenoxyacetic acid), were characterized in dogs. Sulotroban was infused i.v. at 0.06, 0.2, 0.6 and 1.0 mg kg-1 min-1 (plus prime) for 180 min. Arterial blood pressure was reduced significantly during infusion of the 1.0 mg kg-1 min-1 dosage only. Diuresis, characterized by increases in both fractional and absolute urinary excretion of sodium, potassium, chloride and calcium, and decreases in urine osmolality occurred at each of the sulotroban dosages tested. The renal clearance of sulotroban exceeded the glomerular filtration rate, suggesting renal secretion of sulotroban. The transport maximum for sulotroban secretion was approximately 160 micrograms kg-1 min-1. Renal cortical slices from naive dogs accumulated [14C]sulotroban against a concentration gradient. Sulotroban accumulation was blocked by metabolic inhibitors (dinitrophenol and sodium azide) and inhibitors of organic anion transport (probenecid and p-aminohippurate), but not by inhibitors of organic cation transport (cyanine and tetraethylammonium), suggesting that tubular secretion of sulotroban is mediated by an organic anion transport system. It was concluded that: 1) decreases in blood pressure occurred only after high dosages and were associated with high plasma sulotroban concentrations; 2) diuresis occurred at all dosages and may represent a separate pharmacological action unrelated to thromboxane receptor antagonism; and 3) renal excretion of sulotroban in the dog occurs by both filtration and tubular secretion with secretion occurring via an organic acid transporter.
Mann
W A
WA
Department of Investigative Toxicology, Smith Kline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
Welzel
G E
GE
Goldstein
R S
RS
Sozio
R S
RS
Cyronak
M J
MJ
Kao
J
J
Kinter
L B
LB
D000818:Animals; D004285:Dogs; D005260:Female; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008297:Male; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000652:urine*
D013449:Sulfonamides; C040624:sulotroban