Improvement of the oral bioavailability of naltrexone in dogs: a prodrug approach.
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.
Hussain
M A
MA
E.I. du Pont de Nemours & Company, Medical Products Department, Wilmington, DE 19898.
Koval
C A
CA
Myers
M J
MJ
Shami
E G
EG
Shefter
E
E
D000284:Administration, Oral; D000818:Animals; D001241:Aspirin; D001565:Benzoates; D019817:Benzoic Acid; D001682:Biological Availability; D002264:Carboxylic Acids / Q000378:metabolism*; D004285:Dogs; D004952:Esters / Q000378:metabolism*; D005260:Female; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D009271:Naltrexone / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D010421:Pentanoic Acids; D062367:ortho-Aminobenzoates
D001565:Benzoates; D002264:Carboxylic Acids; D004952:Esters; D010421:Pentanoic Acids; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; D009271:Naltrexone; C005566:pivalic acid; D019817:Benzoic Acid; D001241:Aspirin