The urinary excretion profiles of naltrexone in man, monkey, rabbit, and rat.
A gas-chromatographic method has been developed for the simultaneous determination of naltrexone, alpha-naltrexol, and beta-naltrexol as trimethylsiyl derivatives. Analysis of urine from rabbit, monkey, and rat demonstrated that, like man, these species reduce naltrexone primarily to beta-naltrexol. In naltrexone maintenance patients receiving 125 mg po three times per week, an average of 37% of the dose was recovered in 48-hr urine as free naltrexone (0.8%), conjugated naltrexone (7.6%), free beta-naltrexol (16.8%), and conjugated beta-naltrexol (11.8%). Thirty-four percent of the dose appeared in 0-24 hr and 3% during 24-48 hr. The ratio of beta-naltrexol to naltrexone rose from 2 at 0-4 hr to 34-48 hr. Monkeys receiving a daily dose of 12 mg/kg po, chronically, excreted very little free beta-naltrexol and exhibited an apparent sex-related difference in excretion patterns, with females excreting more than twice as much total base as males. Rabbits given a dose of 30 mg/kg ip for 4 days excreted conjugated naltrexone as the predominant urinary metabolite, accounting for 80% of total base recovered in 24 hr. In rats receiving 100 mg/kg po, less than 1% of the administered dose could be accounted for in the 24-hr urine, indicating that although the beta-naltrexol is produced as a urinary metabolite, other means of disposition of the drug must exist. Thus, in man and the monkey, beta-naltrexol is the predominant and persistent urinary metabolite. Urinary excretion profiles of naltrexone differ greatly between species commonly examined for chronic toxicity studies.
The urinary excretion profiles of naltrexone in man, monkey, rabbit, and rat. A gas-chromatographic method has been developed for the simultaneous determination of naltrexone, alpha-naltrexol, and beta-naltrexol as trimethylsiyl derivatives. Analysis of urine from rabbit, monkey, and rat demonstrated that, like man, these species reduce naltrexone primarily to beta-naltrexol. In naltrexone maintenance patients receiving 125 mg po three times per week, an average of 37% of the dose was recovered in 48-hr urine as free naltrexone (0.8%), conjugated naltrexone (7.6%), free beta-naltrexol (16.8%), and conjugated beta-naltrexol (11.8%). Thirty-four percent of the dose appeared in 0-24 hr and 3% during 24-48 hr. The ratio of beta-naltrexol to naltrexone rose from 2 at 0-4 hr to 34-48 hr. Monkeys receiving a daily dose of 12 mg/kg po, chronically, excreted very little free beta-naltrexol and exhibited an apparent sex-related difference in excretion patterns, with females excreting more than twice as much total base as males. Rabbits given a dose of 30 mg/kg ip for 4 days excreted conjugated naltrexone as the predominant urinary metabolite, accounting for 80% of total base recovered in 24 hr. In rats receiving 100 mg/kg po, less than 1% of the administered dose could be accounted for in the 24-hr urine, indicating that although the beta-naltrexol is produced as a urinary metabolite, other means of disposition of the drug must exist. Thus, in man and the monkey, beta-naltrexol is the predominant and persistent urinary metabolite. Urinary excretion profiles of naltrexone differ greatly between species commonly examined for chronic toxicity studies.