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. [13CD3]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 [13CD3]EP, the mean AUC of [13CD3]EP was 16.0 h. microg/mL, while the C(max), T(max), and AUC for [13CD3]SC-70303 acid were 0.744 microg/mL, 0.5 h, and 3.49 h. microg/mL, respectively. After I.V. administration of SC-70303, the AUC for SC-70303 acid was 6.36 h. microg/mL, while the C(max), T(max), and AUC for EP were 2.26 microg/mL, 0.5 h, and 9.48 h. microg/mL, respectively. After oral administration of [13CD3]EP, the C(max), T(max), and AUC for [13CD3]EP were 6.01 microg/mL, 0.5 h, and 27.7 h. microg/mL, respectively, and the corresponding values for [13CD3]SC-70303 acid were 0.972 microg/mL, 0.75 h, and 5.52 h. microg/mL, respectively. After oral administration of SC-70303, the C(max), T(max), and AUC for EP were 1.38 microg/mL, 0.83 h, and 9.29 h. microg/mL, respectively, and the corresponding values for SC-70303 acid were 0.330 microg/mL, 0.67 h, and 2.19 h. microg/mL, respectively. The systemic availability was 90% for [13CD3]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 [13CD3]SC-70303 acid following I.V. administration of [13CD3]EP was 55.0%, while the percentage of dose converted to EP following I.V. administration of SC-70303 was 60.2%.