Naltrexone-3-salicylate (a prodrug of naltrexone): synthesis and pharmacokinetics in dogs.
Naltrexone-3-salicylate (3), a prodrug of naltrexone (1), was prepared by a simple procedure from naltrexone-3-acetylsalicylate (2). The plasma (dog and human) hydrolysis half-life of 3 was found to be approximately 30 min. Compound 2 was previously shown to hydrolyze in dog and human plasma with a fast deacetylation step to 3, followed by slower hydrolysis of 3 to 1 (t1/2, approximately 30 min). Oral naltrexone bioavailability was greatly improved (approximately 30-fold) after oral administration of 3 to dogs, similar to the improvement observed after oral administration of 2. The half-life of naltrexone in dogs after oral administration of 3 was similar to that observed after oral administration of 2 (approximately 1 hr).
Hussain
M A
MA
E. I. du Pont de Nemours & Company, Inc., Medical Products Department, Wilmington, Delaware 19898.
Shefter
E
E
D000818:Animals; D001682:Biological Availability; D004285:Dogs; D005260:Female; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011355:Prodrugs
D011355:Prodrugs; C059502:naltrexone-3-salicylate; D009271:Naltrexone