Interconversion pharmacokinetics of eplerenone, a selective aldosterone blocker, and its lactone-ring open form

The interconversion pharmacokinetics of eplerenone and its lactone-ring open form, SC-70303, were examined in dogs using a stable isotope method. [(CD3)-C-13]EP and SC-70303 were coadministered orally (10 mg/kg) and intravenously (5 mg/kg) as aqueous solutions under fasted conditions. After I.V. administration of [(CD3)-C-13]EP, the mean AUC of [(CD3)-C-13]EP was 16.0 h (.) mug/mL, while the C-max, T-max, and AUC for [(CD3)-C-13]SC-70303 acid were 0.744 mug/mL, 0.5 h, and 3.49 h (.) mug/mL, respectively. After I.V. administration of SC-70303, the AUC for SC-70303 acid was 6.36 h (.) mug/mL, while the C-max, T-max, and AUC for EP were 2.26 mug/mL, 0.5 h, and 9.48 h (.) mug/mL, respectively. After oral administration of [(CD3)-C-13]EP, the C-max, T-max, and AUC for [(CD3)-C-13]EP were 6.01 mug/mL, 0.5 h, and 27.7 h (.) mug/mL, respectively, and the corresponding values for [(CD3)-C-13]SC-70303 acid were 0.972 mug/mL, 0.75 h, and 5.52 h (.) mug/mL, respectively. After oral administration of SC-70303, the Cmax, Tmax, and AUC for EP were 1.38 mug/mL, 0.83 h, and 9.29 h (.) mug/mL, respectively, and the corresponding values for SC-70303 acid were 0.330 mug/mL, 0.67 h, and 2.19 h (.) mug/mL, respectively. The systemic availability was 90% for [(CD3)-C-13]EP and 17.5% for SC-70303 acid. EP and SC-70303 acid were rapidly interconvertible in the dog. The percentage of dose converted to [(CD3)-C-13]SC-70303 acid following I.V. administration of [(CD3)-C-13]EP was 55.0%, while the percentage of dose converted to EP following I.V. administration of SC-70303 was 60.2%. (C) 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:1383-1389, 2002.