PLASMA LEVELS AND EXCRETION OF CODEINE AND METABOLITES IN THE DOG AND MONKEY

¹ Department of Pharmacology, University of Michigan Medical School, Ann Arbor

Experiments on plasma levels and excretion after the subcutaneous administration of 20 mgm./kgm. of codeine to dogs gave the following results: The biologic half-life of free codeine is about two and one-half hours, and that of conjugated codeine about four hours. Urinary excretion accounts for 4 to 11 per cent of the administered drug as free codeine, 42 to 58 per cent as conjugated codeine, and 46 to 69 per cent as total codeine. Fecal excretion amounts to 0.8 to 1.5 per cent of the administered dose of drug, free codeine being the predominant form. Biliary excretion of free and conjugated codeine is negligible. Morphine could not be detected in samples of plasma, urine, feces or bile.

The biologic half-life of both free and conjugated codeine in the plasma of the monkey is approximately two and one-half hours following the subcutaneous injection of 20 mgm./kgm. of codeine. The subcutaneous administration of the latter dose of codeine, or 4 doses of 10 mgm./kgm. at intervals of six hours, resulted in the following observations for the monkey: The urinary recovery expressed as per cent of administered dose of codeine is 3 to 10 per cent as free codeine, 27 to 39 per cent as conjugated codeine, 0.5 to 2 per cent as free morphine, 6 to 10 per cent as conjugated morphine, and 38 to 53 per cent as total metabolites.

Morphine was isolated from monkey urine and identified by mixed melting point of the diacetyl derivative with authentic compound as well as experiments with paper chromatography.

Fecal excretion of codeine and its metabolites is insignificant in the monkey.

It was suggested that the liberated morphine contributes to the low grade physical dependence which develops to codeine in the monkey.