title: A prodrug approach to increasing the oral potency of a phenolic drug. 1. Synthesis, characterization, and stability of an O-(imidomethyl) derivative of 17 beta-estradiol.
abstract: An O-(saccharinylmethyl) prodrug was synthesized to improve the poor oral potency of the phenolic drug 17 beta-estradiol. This O-(imidomethyl) type of prodrug was designed to undergo chemical hydrolysis and to be a poor substrate for enzymatic hydrolysis. At 37 degrees C, it was found to exhibit half-lives of about 13 min in 50% methanol:pH 7.0 (v/v) phosphate buffer, about 3 min in rat plasma, about 15 min in human plasma, and about 50 min in 20% rat liver homogenate. Introduction of the enzyme poison tetraethyl pyrophosphate or the protein denaturant sodium fluoride into rat plasma had no significant effect on the half-life. Thus, the observed increased rate of hydrolysis in biological media is not due to enzymatic catalysis but to a nonspecific solventlike effect. The fact that the rate of hydrolysis in the methanol:buffer exhibited a first-order dependence on the hydroxide ion concentration and that the rate of hydrolysis increased with increasing methanol concentrations up to 70% supported an SN2 mechanism of hydrolysis for the prodrug. These results suggest that an O-(imidomethyl) type prodrug is insensitive to enzymatic catalysis of hydrolysis yet may hydrolyze quickly enough to release 17 beta-estradiol faster than 17 beta-estradiol is conjugated and excreted.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville 32610.
authors.forename: J U
authors.initials: JU
authors.lastname: Patel
authors.forename: R J
authors.initials: RJ
authors.lastname: Prankerd
authors.forename: K B
authors.initials: KB
authors.lastname: Sloan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002021:Buffers; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004355:Drug Stability; D004958:Estradiol / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D000432:Methanol; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010636:Phenols / Q000008:administration & dosage / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012439:Saccharin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D012969:Sodium Fluoride / Q000494:pharmacology
chemical_list: D002021:Buffers; D002800:Cholinesterase Inhibitors; C092441:O-(saccharinylmethyl)estradiol; D009943:Organophosphorus Compounds; D010636:Phenols; D011355:Prodrugs; C005799:tetraethyl pyrophosphate; D004958:Estradiol; D012969:Sodium Fluoride; D012439:Saccharin; D000432:Methanol