Clomipramine metabolites

Oesterheld, J. Kallepalli, B. R. (1997). Grapefruit juice and clomipramine shifting metabolitic ratios./. Clin. Psychopharmacol, 17(1), 62-3. 

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). 

Pirola R, Mundo E, BeUodi L, Bareggi SR. 2002. Simultaneous determination of clomipramine and its desmethyl and hydroxy metabolites in plasma of patients by high-performance liquid chromatography after solid-phase extraction. J Chromatogr B 772(2) 205-210. 

Weigmann H, Hartter S, Hierake C. 1998. Automated determination of clomipramine and its major metabolites in human and rat serum by high-performance liquid chromatography with on-line column-switching. J Chromatogr B Biomed Sci App 710(1-2) 227-233. 

Changing a patient from one MAOI to another, or to a TCA, requires a "wash-out" period of at least 2 weeks to avoid the possibility of a drug interaction. There is evidence to suggest that a combination of an MAOI with clomipramine is more likely to produce serious adverse effects than occurs with other TCAs. Regarding the newer non-tricyclic antidepressants, it is recommended that a "wash-out" period of at least 5 weeks be given before a patient on fluoxetine is given an MAOI this is due to the very long half-life of the main fluoxetine metabolite norfluoxetine. 

A fully automated on-line SPE-HPLC-MS-MS method was developed and validated for the direct analysis of 14 antidepressants and their metabolites in plasma by de Castro et al. [75]. After direct injection of 50pL of plasma without prior sample pre-treatment, gradient RP separation was completed in 14 min, with a sample throughput of 3h. LOQs were estimated to be at 10 ng/ mL. Analytes proved to be stable during sample process with the exception of clomipramine and norclomipramine. 

A 10-year-old boy has a 4-month history of fears of contamination and of refnsing food becanse there might be monster drool in it. He is begnn on clomipramine (CMl), initially 25 mg at night, and the dosage is gradnally increased to three times daily. He complains of mild confusion and dry mouth. A trough blood level of CMl and its demethylated metabolite reveal that CMl is 455 ng/mL and desmethyl CMl is 48 ng/mL. 

Some authors (Flament et ah, 1987) found that response to treatment with clomipramine was correlated with a marked decrease in platelet serotonin concentration and monoamine oxidase (MAO) activity. Changes in cerebrospinal fluid (CSF) neuropeptides and monoamine metabolites have also been described with chronic clomipramine administration (Swedo et ah, 1992 Altemus et ah, 1994). Despite these observations, the exact mechanism of action of serotonergic drugs (and the serotonin hypothesis ) remains unproven, although it is thought they mediate their effects via down-regulation of the presynaptic 5-HTlD autoreceptor (Rauch et ah, 1994). 

Several [Gex-Fabry et al. 1990 Nagy and Johansson 1977], but not all [Vazquez-Rodriguez et al. 1991], research groups found that women achieve higher plasma levels of clomipramine. Some evidence shows that the apparent clearance of the hydroxylated metabolites of clomipramine is slower in women [Gex-Fabry et al. 1990]. 

In contrast, clomipramine s major metabolite, desmethylclomipramine, has a markedly different pharmacological profile from the parent drug ( 35). While clomipramine is a potent inhibitor of serotonin uptake, desmethylclomipramine is a more potent inhibitor of norepinephrine uptake. If clomipramine s value in obsessive-compulsive disorder (OCD) depends on its ability to block 5-HT uptake (and not of norepinephrine), then this effect should be a function of the relative ratio between clomipramine and desmethylclomipramine. Thus, clomipramine could lose its effectiveness for OCD if a patient were an efficient demethylator of this drug. 

Among FICAs, clomipramine is one of the more selective reuptake inhibitors of serotonin. Because plasma levels of its demethylated metabolite (which primarily works through the NE system) can in some patients exceed those of the parent compound, its therapeutic action cannot be solely attributed to serotonin uptake inhibition. 

For these reasons, TDM can serve several roles when using clomipramine. First, it can be used to determine whether clomipramine or its demethlylated metabolite constitutes the majority of the circulating drug. Second, TDM can be used to guide dose adjustment to ensure plasma concentrations equivalent to those seen in adults whose OCD is successfully treated. This approach also ensures that concentration levels do not approach or exceed the toxic threshold for TCAs (i.e., greater than 450 ng/mL). Like adults, children and adolescents demonstrate a wide variability in their capacity to metabolize TCAs. As mentioned earlier, children are usually faster metabolizers of these drugs than adults, so they typically need doses of approximately 2.5 to 3.5 mg/kg. Once puberty has been reached, the required doses can be reduced by as much as 50%. 

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). 

The hypothesis that SSRIs work in OCD by a serotonergic mechanism is also supported by studies showing a strong positive correlation between improvement in obsessive-compulsive symptoms during clomipramine treatment and drug-induced decreases in cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) and platelet serotonin concentrations. Thus, peripheral markers of 5HT function link the symptomatic improvement in OCD symptoms produced by SSRIs to changes in 5HT function. However, these markers do not consistently highlight a 5HT abnormality in untreated patients with OCD,... 

Imipramine, desipramine, amitriptyline, nortriptyline, trimipramine, clomipramine, lofepramine, amoxapine, dosulepin, maprotiline, mianserin, setiptiline, trazodone, fluvoxamine, paroxetine, milnacipram, sulpiride, tandspirone, methylpheni-date, melitracen Amitriptyline, imipramine, trimipramine, clomipramine, citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, reboxetine, viloxazine, doxepin, maprotiline, mianserine, mirtazapine, moclobemide, trazodone, opipramol (and some metabolites)... 

Lew authors described antidepressant analysis in alternative specimens, such as hair or oral fluid. LC-CID-MS and MS/MS mass spectra libraries for identification of several drugs were employed by Muller et al. [32] for the detection of maprotiline, citalopram, and their desmethyl metabolites in authentic hair specimens extracted ions chromatograms were employed for subsequent antidepressant quantification. Also Klys et al. [33] applied LC-MS/MS to the analysis of blood, urine, and hair specimens in a fatal case due to clomipramine overdose in combination with alcohol. Blood clomipramine and norclomipramine concentrations explained the fatal outcome, and hair analysis confirmed that the deceased was on clomipramine treatment for, at least, 12 months prior to his death. With regard to oral fluid analysis, de Castro et al. [34] developed and validated a... 

Banger M, Hermes B, Hartter S et al (1997) Monitoring serum concentrations of clomipramine and metabolites fluorescence polarization immunoassay versus high performance liquid chromatography. Pharmacopsychiatry 30 128-132... 

This case illustrates that the serotonin syndrome can occasionally occur apparently spontaneously in patients taking a single serotonergic drug. The authors were unable to find any reason why the syndrome developed so catastrophically when it did, except for the modestly increased concentrations of clomipramine and its metabolite. 

TCAs DRUG DEPENDENCE THERAPIES-BUPROPION 1. t risk of seizures This risk is marked in elderly people, in patients with a history of seizures, addiction to opiates/cocaine/ stimulants, and in diabetics treated with oral hypoglycaemics or insulin 2. t plasma concentrations of amitriptyline, clomipramine, desipramine, doxepin and imipramine, with risk of toxic effects 1. Bupropion is associated with a dose-related risk of seizures. TCAs lower the seizure threshold. Additive effects when combined 2. Bupropion and its metabolite hydroxybupropion inhibit CYP2D6 1. Extreme caution. The dose of bupropion should not exceed 450 mg/day (or 150 mg/day in those with severe hepatic cirrhosis) 2. Initiate therapy of these drugs at the lowest effective dose... 

Disposition in the Body. Rapidly and completely absorbed after oral administration, but undergoes extensive first-pass N-demethylation to the major active metabolite, monodesmethylclomipramine. Clomipramine and monodesmethylclomipramine are further metabolised by 8-hydroxylation, A -oxidation, and conjugation. About 10 to 15% of a dose is excreted in the urine in 24 hours, of which less than 0.2% is unchanged clomipramine or monodesmethylclomipramine. A total of 45 to 60% of a dose is excreted in the urine over a period of 14 days and about 20 to 30% is slowly eliminated in the faeces. 

Therapeutic Concentration. Plasma concentrations of clomipramine and the desmethyl metabolite vary considerably between individual patients. Steady-state concentrations of clomipramine are usually achieved in about 1 to 2 weeks, but monodesmethylclomipramine may continue to accumulate for 6 weeks or longer. 8-Hydroxyclomipramine and 8-hydroxydes-methylclomipramine have been detected in plasma at significant concentrations during high-dose chronic treatment. 

Metabolized to an active metabolite, desmethyl-clomipramine, a predominantly norepinephrine reuptake inhibitor, by demethylation via CYP450 1A2... 

The only TCA with proven efficacy in OCD Normally, clomipramine (CMI), a pofenf serotonin reuptake blocker, at steady state is metabolized extensively to its active metabolite desmethyl-clomipramine (de-CMI), a potent nonadrenaline reuptake blocker, by the enzyme CYP450 f A2... 

Bengtsson BO, Zliu J, Tliorell LH, Olsson T, Link H, Walinder J (1992) Effects of zimeldine and its metabolites, clomipramine. 

Figure 11.2 Separation of tricyclic antidepressants on a nitrile phase [reproduced with permission from G.L. Lensmeyer, D.A. Wiebe and B.A. Darcey, J. Chromatogr. Sci., 29, 444 (1991)]. Conditions sample, serum extract from a patient who received clomipramine column, 25cm x 4.6mm i.d. stationary phase, Zorbax Cyanopropyl, 5-6pm mobile phase, 1.2ml min water-acetonitrile-acetic acid-n-butylamine (600 400 2.5 1.5) temperature, 45°C UV detector, 254nm. Peaks M = metabolites of clomipramine 1 =trimipramine (internal standard) 2 = des-methylclomipramine 3 = clomipramine.

HT reuptake into the presynaptic neuron. Inhibiting reuptake of 5-HT makes more 5-HT available to postsynaptic receptors and reduces formation of the 5-HT metabolite 5-hydroxyindoleacetic acid. Although other antidepressants, such as imipramine and amitriptyline, inhibit 5-HT reuptake, they are less potent and selective than the SSRIs and clomipramine. Prolonged exposure to increased amounts of 5-HT after chronic antidepressant treatment (2 to 3 weeks) leads to altered responsiveness of postsynaptic 5-HT receptors or presynaptic autoregulatory receptors that govern 5-HT release in specific brain regions. ... 

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