METABOLISM OF IMIPRAMINE INVITRO BY ISOZYME CYP2D6 EXPRESSED IN A HUMAN CELL-LINE, AND OBSERVATIONS ON METABOLITE STABILITY

A metabolism study of imipramine (IMI) has been conducted in vitro wit h 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 t o be unequivocally involved in the N-dealkylation of IMI to desmethyli mipramine (DMI). 2-Hydroxydesipramine was also identified as a trace m etabolite of IMI, but no 10-hydroxyimipramine was detected. The 2-OH-I MI metabolite was unstable and disappeared from metabolic solutions on standing. A procedure involving the 0-acetylation of 2-OH-IMI was dev eloped to minimize this decomposition. When an authentic sample of 10- OH-IMI was subjected to the same acetylation procedure. it was partial ly dehydrated to 10,11-dehydroimipramine, but also underwent unexpecte d degradations to two other products in which the dimethylaminopropyl side-chain was deaminated. Plausible structures for these two decompos ition products are suggested from their gas chromatographic-mass spect rometric behaviour.