The N-demethylation by rat liver of azidomorphine and azidocodeine, new morphine derivatives with low tolerance and dependence capacity in animals and men, was compared to that of morphine. The drugs were administered intraperitoneally, in progressively increasing doses during a period of 27 days, until daily injections of 150 mg/kg of morphine HCl, 3 mg/kg of azidomorphine tartrate and 8 mg/kg of azidocodeine tartrate as maintenance doses were reached. The analgesic ratios of morphine:azidomorphine:azidocodeine were found to be 1:293:13 in the hot plate test. The liver of rats treated for 4 weeks with morphine completely failed to N-demethylate the narcotic drugs. The enzymic N-demethylation of morphine in animals exposed to more prolonged treatment (7-10 weeks) was about 30-40 per cent that of the saline treated controls. Withdrawal of morphine led to a complete restoration of the enzyme activity. In the azidomorphine- and azidocodeine-treated groups however, the N-demethylation capacity of the liver after 4 weeks treatment was only moderately reduced and in rats treated for 7 and 10 weeks, respectively, no decrease in the enzyme activity was observed. The profound difference between azidomorphine, the most potent known analgesic among the semisynthetic morphine derivatives, and morphine demethylation, parallels the difference in their tolerance capacity in animals and man.
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