URINARY-EXCRETION PROFILES OF NALTREXONE IN MAN, MONKEY, RABBIT, AND RAT

Abstract

A gas-chromatographic method was developed for the simultaneous determination of naltrexone, .alpha.-naltrexol and .beta.-naltrexol as trimethylsilyl derivatives. Analysis of urine from rabbit, the rhesus monkey and rat demonstrated that, like man, these species reduce naltrexone primarily to .beta.-naltrexol. In naltrexone maintenance patients receiving 125 mg orally 3 times/wk, an average of 37% of the dose was recovered in 48 h urine as free naltrexone (0.8%), conjugated naltrexone (7.6%), free .beta.-naltrexol (16.8%) and conjugated .beta.-naltrexol (11.8%). Of the dose, 34% appeared in 0-24 h and 3% during 24-48 h. The ratio of .beta.-naltrexol to naltrexone rose from 2 at 0-4 h to 34 at 24-48 h. Monkeys receiving a daily dose of 12 mg/kg orally, 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 i.p. for 4 days excreted conjugated naltrexone as the predominant urinary metabolite, accounting for 80% of total base recovered in 24 h. In rats receiving 100 mg/kg orally, < 1% of the administered dose could be accounted for in the 24 h urine, indicating that although the .beta.-naltrexol is produced as a urinary metabolite, other means of disposition of the drug must exist. 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.