PHYSIOLOGICAL DISPOSITION AND BIOTRANSFORMATION OF [ALLYL-1',3'-C-14] NALOXONE IN RAT AND SOME COMPARATIVE OBSERVATIONS ON NALORPHINE

Abstract

A sensitive method is described for estimating [14C]naloxone in biological materials. After a 1 mg/kg s.c. dose of [14C]naloxone to rats, mean peak levels of drug in the brain (506 ng/g) and plasma (119 ng/ml) were attained within 15 min. No persistence of drug in the 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 .mu.g/g and 1.27 .mu.g/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 concentrations in the liver. The half-life (T1/2) of naloxone and nalorphine in rat brain and plasma with 1 and 10 mg/kg s.c. doses was 0.4 h. With a 10 mg/kg dose significant amounts of radioactivity persisted in tissues but not in plasma 96 h 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 h 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-hydroxynormorphinone, 7,8-dihydro-14-hydroxynormorphine and their conjugates were the metabolites of naloxone. Tentative evidence was obtained for 2 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 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 2 antagonists are discussed.