A prodrug approach to increasing the oral potency of a phenolic drug. Part 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 times as potent, based on 50% effective dose (ED50) values, as 17 beta-estradiol when each was given as an oral dose to ovariectomized rats. Similarly, a significant lowering of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels at 24 h was observed when an ED50 dose of the prodrug was given but not when an equimolar dose of 17 beta-estradiol was given orally. However, when given intravenously, there was no difference in potency between the two drugs. In the bioavailability studies, a significantly longer half-life (approximately 5-7 times) for 17B-estradiol was observed when the prodrug was given orally than when 17 beta-estradiol was given orally or when the prodrug or 17 beta-estradiol were given intravenously. This result was consistent with an observed five-fold enhancement in the oral bioavailability of 17 beta-estradiol when the prodrug was given.
Patel
J
J
Department of Pharmaceutics, University of Florida, Gainesville 32610, USA.
Katovich
M J
MJ
Sloan
K B
KB
Curry
S H
SH
Prankerd
R J
RJ
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D006207:Half-Life; D007275:Injections, Intravenous; D007986:Luteinizing Hormone / Q000097:blood; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012439:Saccharin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D014599:Uterus / Q000187:drug effects
C092441:O-(saccharinylmethyl)estradiol; D011355:Prodrugs; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D012439:Saccharin