PHYSIOLOGIC DISPOSITION OF N-C¹⁴-METHYL-CODEINE IN THE RAT

¹ Department of Pharmacology, College of Medicine, University of Iowa, Iowa City, Iowa

Maximum levels of codeine and its metabolites in plasma and of free codeine in brain appear 15 to 30 min after s. c. adminiRtration of 2 mg/kg (base) of N-C¹⁴-methyl-codeine to Sprague-Dawley male rats. Neither free nor conjugated morphine is found in brain. Conjugated codeine is not detectable in either brain or plasma at any time period. The brain/plasma ratio of free codeine is about 2:1. In 24 hr, 7.6%, 18.5% and 17.7% of injected radioactivity is eliminated as C¹⁴O₂ in expired air from female rats, male rats and male rats with cannulated bile ducts, respectively. Amounts recovered in bile are 1.3% as free codeine, 0.9% as free morphine and 43.1% as conjugated morphine. Percentage recoveries of free codeine, free morphine and conjugated morphine from the respective samples are as follows: urine of male rats with cannulated bile ducts, 62%, 32% and 19.4%; urine of male rats, 7.8%, 7.6% and 23.8%; urine of female rats, 72%, 63% and 44.4%; feces and intestinal content of male rats, 0.8%, 14.3% and 0.0%; feces and intestinal content of female rats, 1.0%, 12.7% and 0.0%. In 24 hr, 94%, 74% and 86% of injected radioactivity is excreted via pulmonary, biliary, intestinal and urinary routes by male rats with cannulated bile ducts, male rats and female rats, respectively. Twenty-four hours after injection, about 2% of administered radioactivity is retained in the body. Metabolites in urine and bile have been identified by paper chromatography.