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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

2-Hydroxyestradiol Is a Prodrug of 2-Methoxyestradiol

Center for Clinical Pharmacology (L.C.Z., R.K.D., E.K.J.), Departments of Medicine and Pharmacology (E.K.J.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; PR Pharmaceuticals (C.A.P., K.M.H., S.D.A.), Fort Collins, Colorado; and Biologistic Services (R.M.F.), Boulder, Colorado

Previous in vivo studies indicate that 2-hydroxyestradiol (2OHE) attenuates cardiovascular and renal diseases. In vitro studies suggest that the biological effects of 2OHE are mediated by 2-methoxyestradiol (2MEOE) after methylation of 2OHE by catechol-O-methyltransferase (COMT). This study tested the hypothesis that in vivo 2OHE is a prodrug of 2MEOE. We administered to male rats i.v. boluses of either 2OHE or 2MEOE and measured plasma levels of 2OHE and 2MEOE by gas chromatography-mass spectrometry at various time points after drug administration. After administration of 2OHE, plasma levels of 2OHE declined extremely rapidly [t_1/2(1) = 0.94 min and t_1/2(2) = 10.2 min] becoming undetectable after 45 min. Concomitant with the disappearance of 2OHE, 2MEOE occurred and then declined [t_1/2(1) = 7.9 min and t_1/2(2) = 24.9 min]. The peak concentration and total exposure (area under the curve) for 2OHE were much lower than for 2MEOE. 2OHE had a much higher plasma clearance (CL) and volume of distribution (V_d) compared with 2MEOE (2OHE: CL = 1215 ml min^-1 kg^-1 and V_d = 17,875 ml/kg; 2MEOE: CL = 50 ml min^-1 kg^-1 and V_d = 1760 ml/kg). After administration of 2MEOE, plasma levels of 2MEOE declined [t_1/2(1) = 2.5 min and t_1/2(2) = 20.2 min] with a plasma CL of 50 ml min^-1 kg^-1 and a V_d of 1500 ml/kg. We could not detect 2OHE in plasma from rats receiving 2MEOE. We conclude that the conversion of 2OHE to 2MEOE is so efficient that in terms of 2MEOE exposure, administration of 2OHE is bioequivalent to administration of 2MEOE itself.

Address correspondence to: Dr. Edwin K. Jackson, 623 Scaife Hall, Center for Clinical Pharmacology, 3550 Terrace St., University of Pittsburgh School of Medicine, Pittsburgh, PA 15261. E-mail: edj{at}pitt.edu

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