title: Metabolism of imipramine in vitro by isozyme CYP2D6 expressed in a human cell line, and observations on metabolite stability.
abstract: A metabolism study of imipramine (IMI) has been conducted in vitro with commercially available human CYP2D6 isozyme expressed in a human AHH-1 TK +/- cell line. This enzyme system catalyzed the anticipated ring-oxidative biotransformation of IMI to 2-hydroxyimipramine (2-OH-IMI). In addition, however, the human CYP2D6 isozyme preparation was found to be unequivocally involved in the N-dealkylation of IMI to desmethylimipramine (DMI). 2-Hydroxydesipramine was also identified as a trace metabolite of IMI, but no 10-hydroxyimipramine was detected. The 2-OH-IMI metabolite was unstable and disappeared from metabolic solutions on standing. A procedure involving the O-acetylation of 2-OH-IMI was developed to minimize this decomposition. When an authentic sample of 10-OH-IMI was subjected to the same acetylation procedure, it was partially dehydrated to 10,11-dehydroimipramine, but also underwent unexpected degradations to two other products in which the dimethylaminopropyl side-chain was deaminated. Plausible structures for these two decomposition products are suggested from their gas chromatographic-mass spectrometric behaviour.
authors.affiliation: Neurochemical Research Unit, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
authors.forename: R T
authors.initials: RT
authors.lastname: Coutts
authors.forename: P
authors.initials: P
authors.lastname: Su
authors.forename: G B
authors.initials: GB
authors.lastname: Baker
authors.forename: M
authors.initials: M
authors.lastname: Daneshtalab
mesh_terms: D000107:Acetylation; D002460:Cell Line; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003891:Desipramine / Q000032:analysis / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007099:Imipramine / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; C033803:2-hydroxyimipramine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D007099:Imipramine; D003891:Desipramine