Physiological disposition and biotransformation of [allyl-1', 3' - 14C naloxone in the rat and some comparative observations on nalorphine.

A sensitive method is described for the estimation of [14C]naloxone in biological materials. After a 1 mg/kg s.c. dose of [14C]naloxone to male Wistar rats, mean peak levels of drug in brain (506 ng/g) and plasma (119 ng/ml) were attained within 15 minutes. No persistence of drug in brain was observed at this dose. After a 10 mg/kg s.c. dose, the peak levels of naloxone in brain and plasma were 4.31 mug/g and 1.27 mug/ml, respectively, and extensive localization of extractable free drug and its minor metabolite, naloxol, occurred in tissues with high levels in kidney, spleen, lung, heart, skeletal muscle and somewhat lower concentration in the liver. The T1/2 of naloxone and nalorphine in rat brain and plasma with 1 and 10 mg/kg s.c. doses was 0.4 hour. With a 10 mg/kg dose, significant amounts of radioactivity persisted in tissues but not in plasma 96 hours after injection. The brain/plasma ratios and degree of plasma-protein binding were significantly higher for naloxone as compared to nalorphine. The amounts of free naloxone excreted as a percentage of the dose in urine and feces 96 hours after injection of the 10 mg/kg s.c. dose were 4.1 and 3.9 (for nalorphine 4.7 and 8.3); conjugated drug 15.4 and 1.2 (for nalorphine 13 and 0.9); total radioactivity 43.3 and 20.9 (for nalorphine 34.8 and 19.2), respectively. Naloxone-3-glucuronide (major), 3-sulfate (minor), naloxol and conjugated naloxol (minor), 7,8-dihydro-14-hydroxynormorphine, 7,8-dihydro-14-hydroxynormorphine and their conjugates were shown to be the metabolites of naloxone. In addition, tentative evidence was obtained for two polar hydroxylated metabolites (with hydroxylation presumably in the 17-side chain or in position 2 of the aromatic nucleus). 7,8-Dihydro-14-hydroxynormorphinone and 2-polar metabolites were also observed in brain. Rapid metabolism of naloxone and rapid elimination are important factors in its short duration of action. Possible relevance of these observations on differential antagonistic properties of these two antagonists are discussed.