ABSTRACT
In an effort to improve the oral bioavailability of naltrexone [17-(cyclopropylmethyl)-4,5 alpha-epoxy-3,14-dihydroxymorphinan-6-one;1], a number of prodrug esters on the 3-hydroxyl group were prepared: the anthranilate (2), acetylsalicylate (3), benzoate (4), and pivalate (5). The oral bioavailability of these prodrugs was determined in dogs. Compounds 2 and 3 exhibited the greatest enhancement of naltrexone bioavailability (45 and 28 times greater than 1, respectively). No correlation was found between the rates of plasma hydrolysis and bioavailability. Naltrexone-3-acetylsalicylate hydrolyzed in human and dog plasma with a fast deacetylation step to naltrexone salicylate followed by a slower hydrolysis step to naltrexone.
Subject(s)
Carboxylic Acids/metabolism , Esters/metabolism , Naltrexone/metabolism , Administration, Oral , Animals , Aspirin , Benzoates , Benzoic Acid , Biological Availability , Dogs , Female , Humans , Hydrolysis , Kinetics , Naltrexone/administration & dosage , Naltrexone/blood , Pentanoic Acids , ortho-AminobenzoatesABSTRACT
Micelle formation by 2-butyl-3-benzofuranyl-4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl ketone hydrochloride was studied by conductance measurements. The CMC was approximately 0.05% and was independent of temperature between 20 and 50degree. The heat of formation for the micelle was calculated to be 6.9 kcal/mole. The unusual solubility behavior of the compound was attributed to its ability to form micelles. Ultracentrifuge studies indicate the molecular weight of the micelle to be approximately 100,000. Anions such as chloride, sulfate, acetate, tartrate, and citrate significantly affect the equilibrium solubility of the compound. NMR spectroscopic data indicate that the solubility behavior, in part, is related to an effect on the CMC of the compound by the anionic environment.