PLASMA LEVELS, URINARY AND FECAL EXCRETION OF MORPHINE IN NON-TOLERANT AND TOLERANT DOGS

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

The administration of 30 mgm./kgm. of morphine to non-tolerant dogs by subcutaneous or intravenous injection was followed by the prompt appearance of free morphine in the plasma. Somewhat higher concentrations and longer duration of detectable levels were observed with the latter route. However, the difference was much more striking in the comparative levels of "bound" morphine. The maximum concentrations of "bound" drug in plasma after intravenous injection were three to four times those observed after subcutaneous administration and were reached more quickly.

After intramuscular injection of the above dose of morphine, plasma concentration—time curves of the free and "bound" forms of the drug were qualitatively similar to those after subcutaneous administration but somewhat higher and more rapidly elevated than in the latter instance. With the method employed there was no detectable free morphine in the plasma after oral administration of 30 mgm./kgm. of morphine although low concentrations of "bound" morphine were observed.

No significant differences were noted between the free and "bound" morphine plasma concentration—time curves of non-tolerant and tolerant dogs after the subcutaneous injection of 30 mgm./kgm. of drug.

A comparison of ten experiments on seven non-tolerant dogs and thirty-one experiments on four tolerant dogs showed no statistical difference in the per cent urinary excretion of either free or "bound" morphine between the two groups. In the case of tolerant dogs there was a greater fecal excretion of morphine. Considering the total excretion (fecal plus urinary) of morphine, there was a trend toward a greater elimination of drug in tolerant animals but the difference was not statistically significant. Accordingly, it is apparent that alterations in the pattern of morphine excretion do not account for the development of tolerance and "physical dependence" in the dog, and it becomes imperative to look to other explanations for the mechanisms of development of these phenomena.