RT Journal Article
SR Electronic
T1 2-Hydroxyestradiol Is a Prodrug of 2-Methoxyestradiol
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1093
OP 1097
DO 10.1124/jpet.103.062505
VO 309
IS 3
A1 Lefteris C. Zacharia
A1 Claude A. Piché
A1 Robert M. Fielding
A1 Kathleen M. Holland
A1 S. Dean Allison
A1 Raghvendra K. Dubey
A1 Edwin K. Jackson
YR 2004
UL http://jpet.aspetjournals.org/content/309/3/1093.abstract
AB 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 [t1/2(1) = 0.94 min and t1/2(2) = 10.2 min] becoming undetectable after 45 min. Concomitant with the disappearance of 2OHE, 2MEOE occurred and then declined [t1/2(1) = 7.9 min and t1/2(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 (Vd) compared with 2MEOE (2OHE: CL = 1215 ml min-1 kg-1 and Vd = 17,875 ml/kg; 2MEOE: CL = 50 ml min-1 kg-1 and Vd = 1760 ml/kg). After administration of 2MEOE, plasma levels of 2MEOE declined [t1/2(1) = 2.5 min and t1/2(2) = 20.2 min] with a plasma CL of 50 ml min-1 kg-1 and a Vd 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. The American Society for Pharmacology and Experimental Therapeutics