Prodrugs for improved oral beta-estradiol bioavailability.
Prodrugs of beta-estradiol (1) were prepared with the objective of improving its oral bioavailability. beta-Estradiol-3-acetylsalicylate (2), beta-estradiol-3-salicylate (3), and beta-estradiol-3-anthranilate (4) were synthesized. With these prodrugs the 3-phenolic hydroxy group of estradiol was protected, so that first-pass conjugative metabolism could be reduced. Prodrug hydrolysis rates in dog and human plasma in vitro were determined. Deacetylation of estradiol-3-acetylsalicylate was much more rapid than its hydrolysis to estradiol. In dogs, oral estradiol bioavailability after administration of 2 and 4 was 17-fold and 5-fold higher, respectively, than after oral 1.
Hussain
M A
MA
Du Pont Pharmaceuticals, Medical Products Department, Wilmington, Delaware 19898.
Aungst
B J
BJ
Shefter
E
E
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D004958:Estradiol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D011355:Prodrugs
D011355:Prodrugs; D004958:Estradiol