Imipramine metabolism

Maynard, G.L. and Soni, P. (1996) Thioridazine interferences with imipramine metabolism and measurement. Ther Drug Monit 18 729-731. 

Chiba K, Saitoh A, Koyama E, et al. The role of (S)-mephenytoin 4 -hydroxylase in imipramine metabolism by human bver microsomes a two-enzyme analysis of N-demethylation and 2-hydroxylation. Br J Cbn Pharmacol 1994 37 237-242. 

Skjelbo E, Brosen K. Inhibitors of imipramine metabolism by human liver microsomes. Br J Clin Pharmacol 1992 34 256-261. 

LABETALOL PROPANOLOL IMIPRAMINE T imipramine levels with labetalol and propanolol Uncertain at present. Postulated that imipramine metabolism 1 by competition at CYP2D6 and CYP2C8 Monitor plasma levels of imipramine when initiating beta-blocker therapy... 

Albers LJ, Reist C, Vu RL, Fujimoto K, Ozdemir V, Helmeste D, Poland R, Tang SW. Effect of venlafaxine on imipramine metabolism. Psychiatry Res 2000 96(3) 235-43. 

Rouer, E., A. Lemoine, T. Cresteil, P. Rouet, and J.P. Leroux (1987). Effects of genetically or chemically induced diabetes on imipramine metabolism. Respective involvement of flavin monooxygenase and cytochrome P450-dependent monooxygenases. Drug Metab. Dispos. 15, 524-528. 

Lemoine A, Gauthier JC, Azoulay D et al. Major pathway of imipramine metabolism is catalyzed by cytochromes P450 1A2 and P450 3A4 in human liver. Mol Pharmacol 1993 43 827-832. 

A patient suffering from a depressive disorder is being treated with imipramine. If he uses diphenhydramine for allergic rhinitis, a drug interaction is likely to occur because (A) Diphenhydramine inhibits imipramine metabolism... 

Fa3mor SM, Espina V. Fluoxetine inhibition of imipramine metabolism. Clin Chem (1989) 35,1180. 

Albers LJ, Reist C, Helmeste D, Vu R, Tang SW. Paroxetine shifts imipramine metabolism. 

All TCAs are either secondary- or tertiary-amines of a dibenzazepine nucleus (Fig. 20.3), and they all inhibit neuronal reuptake of noradrenaline and/or 5-HT but are much less potent as dopamine reuptake blockers. A common claim is that secondary amines (e.g. desipramine) are preferential inhibitors of noradrenaline uptake whereas the tertiary derivatives (e.g. imipramine, doxepin and amitryptyline) preferentially inhibit 5-HT uptake. However, when Richelson and Pfenning (1984) actually compared the effects of a wide range of antidepressants on the synaptosomal uptake of [ H]monoamines in vitro, and compared their A s, instead of merely ranking /C50S collected from different studies, they found that tertiary- and secondary-substituted compounds were equi-potent inhibitors of [ H]noradrenaline uptake. Moreover, all the TCAs turned out to be more potent inhibitors of [ H]noradrenaline than of [ H]5-HT uptake. Tertiary amines are even less convincing inhibitors of 5-HT reuptake in vivo, because any such action is diminished by their metabolism to secondary amines (e.g. imipramine to desipramine amitriptyline to nortriptyline). Only clomipramine retains any appreciable 5-HT uptake blocking activity in vivo with (an unimpressive) five-fold selectivity for 5-HT versus noradrenaline. 

Metabolism converts a lipophilic molecule into a more hydrophilic (water-loving) metabolite that can be excreted in urine by the kidneys. In the majority of cases the drug is detoxified, or made pharmacologically inactive by this metabolic breakdown. However, a few drugs need to be metabolised to become psychoactive for instance, the sedative-hypnotic chloral hydrate is converted to the active metabolite trichloroethanol. In this case the parent molecule is referred to as a prodrug. With many drugs, both the parent compound and its metabolites are psychoactive. An example of this is the tricyclic antidepressant imipramine which is metabolised to desipramine, with... 

Coutts RT, Su P, Baker GB, Daneshtalab M. 1993. Metabolism of imipramine in vitro by isozyme CYP2D6 expressed in a human cell line, and observations on metabolite stability. J Chromatogr B Biomed Appl 615 265. 

The true tricyclics are often subdivided into tertiary and secondary amine groups. Structurally, the difference lies in the length of side chains branching off the basic three-ringed hub of the molecule. Clinically, side effects are most common and most severe with the tertiary amine medications such as amitriptyline, imipramine, and doxepin. The secondary amines are generally better tolerated. It should be added that two of the tertiary amine TCAs, amitriptyline and imipramine, are metabolized... 

The metabolism and elimination of TCAs takes several days to occur, the elimination half-life ranging from 20 hours for amitriptyline to 80 hours for protriptyline. The half-life values for the desmethylated metabolites such as desmethylimipramine and nortriptyline are approximately twice those of the parent compounds imipramine and amitriptyline. It is also well established that the half-life values of the TCAs are considerably greater in the elderly, which predisposes such patients to a greater possibility of severe side effects. 

Iproniazid, an MAOI no longer available because of its hepatotoxicity, was the first effective antidepressant to be discovered it was introduced shortly before the discovery of imipramine. All MAOIs are presumed to have a similar mode of action, namely to inhibit the intra- and interneuronal metabolism of the biogenic amine neurotransmitters (noradrenaline, dopamine and serotonin). These amines are primarily metabolized by MAO-A (noradrenaline and serotonin) or MAO-B (dopamine). The irreversible MAOIs are inhibitors of MAO-A while selegiline (deprenyl), used as an adjunctive treatment for Parkinson s disease, is a selective, irreversible inhibitor of MAO-B. 

This chapter describes the structure and neurochemical function of TCAs, metabolism and significant interactions with other medications, side effects, and specific recommendations for monitoring of side effects in children and adolescents. Because of the recent concern regarding the sudden deaths of children stabilized on TCAs, particular attention will be paid to the potential cardiovascular effects of these medications. The chapter will focus on the five TCA medications that have been most widely used in children amitriptyline (AMI), nortriptyline (NT), imipramine (IMI), desipratnine (DMI), and clomipramine (CMI). 

Ball, S.E., Ahem, D., Scatina, J., and Kao, J. (1997) Venlafaxine in vitro inhibition of CYP2D6 dependent imipramine and desipra-mine metabolism comparative studies with selected SSRIs, and... 

Gram LE, Christiansen J Pirst-pass metabolism of imipramine in man. Clin Pharmacol Ther 17 555-563, 1975... 

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