303-70-8Relevant academic research and scientific papers
Metabolism of imipramine by microorganisms
Hufford,Capiton,Clark,Baker
, p. 151 - 155 (1981)
The microbial metabolism of imipramine was studied using selected fungal organisms. The major microbial metabolites were isolated, and their structures were established by spectroscopic analyses (particularly 13C-NMR) and by comparison with authentic samples. The microbial metabolites identified included 2-hydroxyimipramine, 10-hydroxyimipramine, iminodibenzyl, imipramine-N-oxide, and desipramine; these metabolites also have been found in mammalian metabolism studies.
Reappraisal of human CYP isoforms involved in imipramine N- demethylation and 2-hydroxylation: A study using microsomes obtained from putative extensive and poor metabolizers of S-mephenytoin and eleven recombinant human CYPs
Koyama, Eriko,Chiba, Kan,Tani, Masanao,Ishizaki, Takashi
, p. 1199 - 1210 (2007/10/03)
Cytochrome P450 (CYP) involved in the two major pathways of imipramine (IMI) was reappraised using human liver microsomes phenotyped for S- mephenytoin 4'-hydroxylation in vitro and 11 recombinant human CYP isoforms. Individual Eadie-Hoffstee plots for IMI N-demethylation and 2-hydroxylation showed a monophasic profile in microsomes obtained from three putative S- mephenytoin poor metabolizer (PM) livers, whereas the plots gave a biphasic relationship (except for one case in 2-hydroxylation) in those from the three extensive metabolizer (EM) livers. Effects of CYP-selective inhibitor/substrate probes on the two metabolic reactions were examined at the two IMI concentrations (2 and 400 μM) with microsomes obtained from the two PM and three EM livers. S-mephenytoin inhibited IMI N-demethylation by 50% at the low concentration in microsomes from the EM livers with no discernible effect on this pathway in those from the PM livers. Furafylline inhibited the N-demethylation by about 60% at the low and high substrate concentrations in microsomes from both the EM and PM livers. Quinidine abolished the 2-hydroxylation at the low and high concentrations in microsomes from both the EM and the PM livers. Among the recombinant human CYPs, CYP2C19, 2C18, 2D6, 1A2, 3A4 and 2B6 in rank order catalyzed the N- demethylation, whereas CYP2D6, 2C19, 1A2, 2C18 and 3A4 catalyzed the 2- hydroxylation. The K(m) values obtained from recombinant CYP2C19 and 1A2 approximated those of the high- and low-affinity components from human liver microsomes for IMI N-demethylation, respectively. For IMI 2-hydroxylation, the respective K(m) values obtained from recombinant CYP2D6 and 2C19 were close to those of the high- and low-affinity components from human liver microsomes. Our human liver microsomal study using the near-therapeutic IMI concentration (2 μM) suggests that 1) CYP2C19 and 1A2 are involved in the N- demethylation and the 2-hydroxylation is mediated exclusively by CYP2D6 and partially by CYP2C19 in the EM livers, and 2) CYP1A2 and 2D6 play a major role in IMI N-demethylation and 2-hydroxylation, respectively, in the PM livers. Our recombinant human CYP isoform study, in general, supports this conclusion.
