Studies on the Metabolism of 3-O-tert.-Butylmorphine, a New Morphine Derivative, by the Rat

1. The O-dealkylation of 3-O-tert.-butylmorphine, a new derivative of morphine, has been compared to the O-dealkylation of codeine by the rat. Rats were given either 3-O-tert.-butylmorphine or codeine intraperitoneally and 24 h urine samples were collected and analysed for morphine by a quantitative gas chromatographic procedure. With codeine, about 7% of the dose was excreted as morphine. In contrast, about 0.3% of a dose of 3-O-tert.-butylmorphine was recovered from urine as morphine. These results indicate that, unlike codeine, 3-O-tert.-butylmorphine is not O-dealkylated to any appreciable extent by the rat. 2. Three metabolites of 3-O-tert.-butylmorphine have been recovered from rat urine, resolved by gas chromatography and identified by mass spectroscopy as 3-O-tert.-butylnormorphine, 3-O-(2-hydroxymethyl-2-propyl)morphine and 3-O-(2-hydroxymethyl-2-propyl)normorphine. The identities of the last two metabolites were confirmed by comparison of their mass spectra with the mass spectra of synthetic reference compounds. 3. Compared with codeine and morphine, 3-O-tert.-butylmorphine was virtually devoid of analgesic or antitussive properties, and was inactive as a morphine antagonist.