Metabolism of imipramine in vitro: synthesis and characterization of N-hydroxydesmethylimipramine

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Abstract
1. The synthesis of N-hydroxydesmethylimipramine via the corresponding primary hydroxylamine and oxime is described. 2. The N-oxygenated products are unstable to g.l.c. analysis without prior derivatization; the decomposition products are identified by g.l.c.-mass spectrometry. 3. N-Hydroxydesmethylimipramine is shown to be a metabolite of imipramine and desmethylimipramine on incubation of either with fortified 9000g liver homogenates of male New Zealand white rabbits. The metabolic product is characterized by mass spectrometry and n.m.r. 4. Didesmethylimipramine is shown to undergo metabolic α-C-oxidation, to yield the carboxylic acid, 3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)propionic acid, but not N-oxidation. 5. N-Hydroxydesmethylimipramine is metabolically reduced to desmethylimipramine and metabolized further to 10-hydroxydesmethylimipramine, 2-hydroxydesmethylimipramine and the carboxylic acid. 6. The possible role of N-hydroxydesmethylimipramine and 3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)propionic acid in the formation of iminodibenzyl is discussed.