Imipramine metabolites

Imipraminoxide is an imipramine metabolite. In a comparison with the parent drug, efficacy was identical adverse effects were of the same type but possibly less frequent (1). 

Imlpramine Metabolites - The desmethyl- (DMI) and the 2-hydroxyImipramine are the major metabolites of imip-ramine. In addition, sixteen others have been detected in rat liver microsomes O, Theobald et al.51 have reported on the central and peripheral effects of six imipramine metabolites in several animal species. 

Extracted desipramine, 2-hydroxydesipramine, 2-hydroxyimipramine, imipramine, metabolites, nortriptyline... 

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... 

The first two antidepressants, iproniazid and imipramine, were developed in the same decade. They were shown to reverse the behavioural and neurochemical effects of reserpine in laboratory rodents, by inhibiting the inactivation of these monoamine transmitters (Leonard, 1985). Iproniazid inhibits MAO (monoamine oxidase), an enzyme located in the presynaptic neuronal terminal which breaks down NA, 5-HT and dopamine into physiologically inactive metabolites. Imipramine inhibits the reuptake of NA and 5-HT from the synaptic cleft by their transporters. Therefore, both of these drugs increase the availability of NA and 5-HT for binding to postsynaptic receptors and, therefore, result in enhanced synaptic transmission. Conversely, lithium, the oldest but still most frequently used mood stabiliser (see below), decreases synaptic NA (and possibly 5-HT) activity, by stimulating their reuptake and reducing the availability of precursor chemicals required in the biosynthesis of second messengers. 

Desipramine An active metabolite of imipramine that is more selective for inhibiting noradrenaline reuptake into the presynaptic neuron. 

We employed various substrates to check for MFO in two bivalve species, a salt water mussel (Mytilus edulis) and a fresh water clam (Anodonta sp). Cytochrome P-450 was also studied. Organisms were exposed to 100 PPM Venezuelan crude in a stagnant system for up to one month. Enzyme assays were carried out with digestive gland 9000 g homogenates (17) and cytochrome P-450 analysis, with microsomes (21). The hydrocarbon substrates investigated included 1I+C-labelled benzo(a)pyrene, fluorene, anthracene, and naphthalene. The method used for separation of BP metabolites by thin layer radiochromatography has been described (7). The metabolite detection method for the other aromatic hydrocarbons was essentially the same except methylene chloride was used as metabolite extractant as well as TLC developer. Besides the hydrocarbon substrates, we also checked for other MFO reactions, N-dealkylase with C-imipramine (22) and 0-dealkylase with ethoxycoumarin (15). 

Solid phase extraction (SPE) has been used to efficiently extract several types of antidepressants, which can then be conveniently analyzed on GC-NPD. One assay extracted and analyzed viloxazine, venlafaxine, imipramine, desipramine, sertraline, and amoxapine from whole blood in one procedure (Martinez et al., 2002). The same laboratory analyzed fluoxetine, amitriptyline, nortriptyline, trimipramine, maprotiUne, clomipramine, and trazodone in whole blood in one assay (Martinez et al., 2003). SPE has also been used for the simultaneous analysis of TCAs and their metabolites by de la Torre et al. (1998). 

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. 

Rodriguez Flores, J., Berzas Nevado, J. J., Contento Salcedo, A. M., and Cabello Diaz, M. P. (2005). Nonaqueous capillary electrophoresis method for the analysis of tamoxifen, imipramine and their main metabolites in urine. Talanta 65, 155-162. 

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. 

Maprotiline (Ludiomil) and amoxapine (Asendin) are heterocyclic antidepressant agents that are not members of the tricyclic family. However, their pharmacology is so similar to that of the tricyclic amines that they are included for discussion purposes with this class of agents. Desipramine and nortriptyline are major metabolites of imipramine and amitriptyline, respectively. 

Since that time, many other tricyclic antidepressants have been studied and put into use. They are all structurally related to imipramine. The active metabolite of imipramine is desipramine. This means that imipramine breaks down into desipramine in the body, and the resulting desipramine actually improves mood. Because their structures are so similar, scientists assume that they have a similar action in the body. 

Precursor therapy as a means of increasing dopaminergic transmissions is limited to L-tyrosine and L-dopa. Although under basal conditions the exogenous administration of tyrosine leads to specific enhancement of noradrenergic transmission, it can enhance dopaminergic transmission in conditions of DA deficiency [Kapur and Mann 1992). Only one adequately controlled clinical trial has been reported, in which 65 patients with major depression were randomly selected to treatment for 4 weeks with oral L-tyrosine 100 mg/kg/day, imipramine 2.5 mg/kg/day, or placebo [Gelenberg et al. 1990). Tyrosine increased and imipramine decreased excretion of the main metabolite of NA, but no evidence was found that tyrosine had antidepressant activity in contrast with imipramine. 

Clinically meaningful plasma levels are available for imipramine, desipramine, and nortriptyline. For imipramine, the sum of the plasma levels of imipramine and the desmethyl metabolite (desipramine) should be greater than 200-250 ng/mL. Desipramine levels should be greater than 125 ng/mL. A therapeutic window has been noted for nortriptyline, with optimal response between 50 and 150 ng/mL. These therapeutic levels are based on steady-state concentrations, which are reached after 5-7 days of administration of these medications. Blood should be drawn approximately 10-14 hours after the last dose of medication. 

Another important situation occurs when the parent drug is biotransformed into a less efficacious and possibly more toxic metabolite. For example, if the concentration of the hydroxylated metabolite of imipramine (2-hydroxyimipramine) were increased, this TCA could lose its effectiveness while simultaneously increasing in toxicity (38). 

Well-controlled studies have found lofepramine to be superior to placebo and comparable with amitriptyline, imipramine. and maprotiline ( 109). It may be better tolerated than earlier HCAs, especially by elderly patients. Desipramine is its major metabolite ( Table 7-4 and Table 7-6). 

The ratio of parent drug to desmethylated metabolite at steady-state has been reported to range from 0.47 to 0.70 for imipramine desipramine and from 0.83 to 1.16 for amitriptyline nortriptyline. These typical ratios can be used to help distinguish between an acute overdose (increased ratios) versus a steady-state situation (normal ratios). 

As a results of these studies, clinicians have proposed that switching to reboxetine or bupropion might a useful strategy given that these antidepressants share the ability with desipramine and imipramine to block NE uptake. Nevertheless, only one small open label study has been done to test this possibility ( 365). If bupropion is to be used in patients switched from an ineffective trial of fluoxetine, the dose should be kept low for several weeks to allow for the clearance of fluoxetine and norfluoxetine. Case reports indicate that fluoxetine can elevate levels of the active metabolites of bupropion, which, in turn, could mediate an increase risk of adverse effects (366). 

Preskorn SH, Bupp S, Weller E, et al. Plasma levels of imipramine and metabolites in 68 hospitalized children. J Am Acad Child Adolesc Psychiatry 1989 28 373-375. 

The TCAs resemble the SNRIs in function, and their antidepressant activity is thought to relate primarily to their inhibition of 5-HT and norepinephrine reuptake. Within the TCAs, there is considerable variability in affinity for SERT versus NET. For example, clomipramine has relatively very little affinity for NET but potently binds SERT. This selectivity for the serotonin transporter contributes to clomipramine s known benefits in the treatment of OCD. On the other hand, the secondary amine TCAs, desipramine and nortriptyline, are relatively more selective for NET. Although the tertiary amine TCA imipramine has more serotonin effects initially, its metabolite, desipramine, then balances this effect with more NET inhibition. 

Imipramine Mixed and variable blockade of NET and SERT Like SNRIs plus significant blockade of autonomic nervous system and histamine receptors Major depression not responsive to other drugs chronic pain disorders incontinence obsessive-compulsive disorder (clomipramine) Long half-lives CYP substrates active metabolites Toxicity Anticholinergic, G.-blocking effects, sedation, weight gain, arrhythmias, and seizures in overdose Interactions CYP inducers and inhibitors... 

FIGURE 6—11. Certain tricyclic antidepressants, especially secondary amines such as clomipramine and imipramine, are substrates for CYP450 1A2. This enzyme converts the tricyclics into active metabolites by demethylation to form desmethylclomipramine and desipramine, respectively. 

One CYP450 enzyme of relevance to antidepressants is 1A2 (Figs. 6—11 and 6—12). Certain tricyclic antidepressants (TCAs) are substrates for this enzyme, especially the secondary amines such as clomipramine and imipramine (Fig. 6—11). CYP450 1A2 demethylates such TCAs, but does not thereby inactivate them. In these cases, the desmethyl metabolite of the TCA (e.g., desmethylclomipramine and desipramine) is still an active drug (Fig. 6—12). 

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