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New morphine metabolites in the urine of guinea pigs, rats, rabbits, cats, monkeys, and humans were isolated with column chromatography, solvent extraction, and TLC and identified with TLC, GLC, and GLC-mass spectrometry. In addition to the known morphine metabolites, morphine N-oxide was isolated from the urine of guinea pigs, and alpha- and beta-dihydromorphines were isolated or detected in the urine of guinea pigs, rats, and rabbits. Monohydroxymorphine was identified tentatively in the urine of guinea pigs, rats, rabbits, and cats. Dihydroxymorphine was identified tentatively in the urine of guinea pigs, rats, and possibly, rabbits. Finally, beta- or gamma-isomorphine was identified tentatively in the urine of guinea pigs. The newly described morphine metabolites may be involved in some long lasting pharmacological effects of morphine.

Biotransformation of morphine to dihydromorphinone and normorphine was studied in several mammalian species. Free and total dihydromophinone, morphine, and normorphine in the urine were determined, as propionyl derivatives, with a gas-chromatographic technique. Dihydromorphinone was detected as a morphine metabolite in the acid-hydrolyzed urine of all species studied except the dog and morphine-dependent man. Normorphine in both free and conjugated forms was detected in the urine of all species studied. The degree of biotransformation of morphine to dihydromorphinone in the guinea pig did not change during chronic administration of morphine sulfate, 25 mg/kg, daily for 28 days. The small amounts of dihydromorphinone and normorphine produced as metabolites make it unlikely that they play any significant role in the modification of the pharmacologic effects of morphine.

Morphine, morphine glucuronide, morphine ethereal sulfate, normorphine and total normorphine in three consecutive 24-hour urines of four morphine-dependent subjects receiving morphine sulfate 60 mg s.c. q.i.d. have been determined with thin-layer chromatography and gas-liquid chromatography. With thin-layer chromatography the mean daily excretion of free morphine was 10% of the administered dose; morphine glucuronide, 65%; total (free and acid hydrolyzable conjugate) morphine 85%; and total normorphine, 3.5%. With gas-liquid chromatography, the percentage excretion for free morphine was 10%; total morphine, 74%; free normorphine, 1%; and total normorphine, 4%. The excretion of total drug was linearly related to the volume of the daily urine output.

Morphine metabolites were isolated with column chromatography on a resin and neutral aluminum oxide and TLC from the urine of morphine-dependent subjects maintained on morphine sulfate at a dose of 240 mg/day. These metabolites were characterized as morphine 3-glucuronide, morphine 6-glucuronide, morphine 3,6-diglucuronide, morphine 3-ethereal sulfate, normorphine, normorphine 6-glucuronide, and, possibly, normorphine 3-glucuronide by free phenol and glucuronide tests, enzymatic hydrolysis, GLC, TLC, UV spectroscopy, and GLC--mass spectrometry.