Further metabolic studies of codeine and morphine in mice pretreated with sympathomimetics

The effects of ephedrine and phenylpropanolamine (PPA) on the 24 h urinary excretion of morphine, codeine and their metabolites, and on the plasma and brain disposition of morphine and codeine at steady state in mice were studied. Morphine-3-glucuronide was the major urinary metabolite in morphine treated animals, while for codeine treated animals norcodeine and morphine-3-glucuronide were the major metabolites. In all cases percentage of drug excreted unchanged was 10-15% of the administered dose. Ephedrine or PPA pretreatment had no apparent effect on these parameters. The metabolic ratios for the different pathways were comparable in all treatment groups. Steady-state plasma and brain concentration-time profiles of codeine and morphine also showed marked similarity in all treatment groups. Apparently, ephedrine or PPA pretreatment has no effect on the disposition of morphine and codeine in mice. The results are discussed from the perspective of our earlier findings of dependence on cough mixtures containing opioids and sympathomimetics.