Absorption and disposition of a selective aldosterone receptor antagonist,eplerenone, in the dog

Purpose. The present study was conducted to characterize the pharmacokineti cs 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, intraduod enal, 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 cle arance of EP were 2.21 hr and 0.329 l/kg/hr, respectively. Plasma concentra tions of the open lactone ring form were lower than EP concentrations regar dless of the route of administration. The C-14 AUC in red blood cells was a pproximately 64% and 68% of the plasma AUC for i.v. and oral doses. Percent ages 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 excr eted 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 foll owing i.v. and oral doses. Conclusions. EP was rapidly and efficiently absorbed throughout the gastroi ntestinal tract, resulting in a good systemic availability. The drug did no t preferentially accumulate in red blood cells. EP was extensively metaboli zed; however, first-pass metabolism after oral and rectal administration wa s minimal. EP and its metabolites appear to be highly excreted in the bile.