Absorption and disposition of a selective aldosterone receptor antagonist, eplerenone, in the dog.
OBJECTIVE
The present study was conducted to characterize the pharmacokinetics of eplerenone (EP), a selective aldosterone receptor antagonist, and its open lactone ring form in the dog.


METHODS
Pharmacokinetic studies of EP were conducted in dogs following i.v., oral, and rectal dosing (15 mg/kg) and following intragastric, intraduodenal, intrajejunal, and intracolonic dosing (7.5 mg/kg).


RESULTS
After oral administration, the systemic availability of EP was 79.2%. Systemic availabilities following administration via other routes were similar to that following oral administration. The half-life and plasma clearance of EP were 2.21 hr and 0.329 l/kg/hr, respectively. Plasma concentrations of the open lactone ring form were lower than EP concentrations regardless of the route of administration. The C-14 AUC in red blood cells was approximately 64% and 68% of the plasma AUC for i.v. and oral doses. Percentages of the dose excreted as total radioactivity in urine and feces were 54.2% and 40.6%, respectively, after i.v. administration, and 40.7% and 52.3%, respectively, after oral administration. The percentages of the dose excreted in urine and feces as EP were 13.7% and 2.5%, respectively, after i.v. administration, and 2.1% and 4.6% after oral administration, respectively. Approximately 11% and 15% of the doses were excreted as the open form following i.v. and oral doses.


CONCLUSIONS
EP was rapidly and efficiently absorbed throughout the gastrointestinal tract, resulting in a good systemic availability. The drug did not preferentially accumulate in red blood cells. EP was extensively metabolized; however, first-pass metabolism after oral and rectal administration was minimal. EP and its metabolites appear to be highly excreted in the bile.
Cook
C S
CS
Metabolism and Safety Evaluation, Pharmacia, Skokie, IL 60077, USA. chyung.s.cook@monsanto.com
Zhang
L
L
Fischer
J S
JS
D000284:Administration, Oral; D000285:Administration, Rectal; D000818:Animals; D001825:Body Fluid Compartments; D004285:Dogs; D000077545:Eplerenone; D005243:Feces; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D009061:Mouth Mucosa / Q000378:metabolism; D013148:Spironolactone / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013270:Stomach
D000451:Mineralocorticoid Receptor Antagonists; C424563:SC70303; D013148:Spironolactone; D000077545:Eplerenone