A pharmacokinetics and metabolism study was conducted in eight healthy human volunteers. After oral administration of [14C]eplerenone (EP) at a dose of 100 mg per person as an aqueous solution, blood, saliva, breath, urine, and fecal samples were collected at various time points. All matrices were analyzed for total radioactivity and/or for EP and its open-lactone-ring form (EPA). EP was well absorbed, and a mean EP Cmax of 1.72 mug/ml was achieved 1.2 h postdose. After the Cmax, plasma concentrations of EP declined with a half-life of 3.0 h. Plasma concentrations of EPA were much lower than EP concentrations, and the area under the plasma-concentration time curve (AUC) for EPA was only 4% of the EP AUC. Plasma protein binding was moderate (33-60%) but concentration-dependent over the therapeutic concentration range. EP and its metabolites did not preferentially partition into the red blood cells and blood concentrations of total radioactivity were lower than plasma concentrations. Approximately 66.6% and 32.0% of the radioactive dose were excreted in urine and feces, respectively. The majority of urinary and fecal radioactivity was due to metabolites, indicating extensive metabolism of EP. The major metabolic pathways were 6beta- and/or 21-hydroxylation and 3-keto reduction. There was no evidence for any alteration of the 9,11-epoxide ring or the methyl ester. As a percentage of dose, the primary metabolic products excreted in urine and feces included 6beta-hydroxy-EP (6beta-OHEP) (32.0%), 6beta,21-OHEP (20.5%), 21-OHEP (7.89%), and 2alpha,3beta,21-OHEP (5.96%). The amounts of the other metabolites excreted were less than 5% each.