A PRODRUG APPROACH TO INCREASING THE ORAL POTENCY OF A PHENOLIC DRUG .2. PHARMACODYNAMICS AND PRELIMINARY BIOAVAILABILITY OF AN ORALLY-ADMINISTERED O-(IMIDOMETHYL) DERIVATIVE OF 17-BETA-ESTRADIOL

The O-saccharinylmethyl prodrug of 17 beta-estradiol was about nine ti mes as potent, based on 50% effective dose (ED(50)) values, as 17 beta -estradiol when each was given as an oral dose to ovariectomized rats. Similarly, a significant lowering of follicle-stimulating hormone (FS H) and luteinizing hormone (LH) levels at 24 h was observed when an ED (50) dose of the prodrug was given but not when an equimolar dose of 1 7 beta-estradiol was given orally. However, when given intravenously, there was no difference in potency between the two drugs. In the bioav ailability studies, a significantly longer half-life (similar to 5-7 t imes) for 17 beta-estradiol was observed when the prodrug was given or ally than when 17 beta-estradiol was given orally or when the prodrug or 17 beta-estradiol were given intravenously. This result was consist ent with an observed five-fold enhancement in the oral bioavailability of 17 beta-estradiol when the prodrug was given.