Clomipramine pharmacokinetics

Imipramine, a TCA, was the first pharmacological agent noted to treat panic disorder (Klein 1964). Other TCAs, notably clomipramine, have also been found to have significant anxiolytic properties (den Boer et al. 1990 Modigh 1992). Studies of ethnic differences in the pharmacokinetics of the TCAs in... 

A more common approach in difficult to treat cases would be the combination of clomipramine with a SSRI several reports lend support to this practice (Simeon and Thatte, 1990 Figueroa et al., 1998). In this situation, careful attention to the potential pharmacokinetic interactions discussed above are recommended. Sertraline and citalopram are least likely to elevate tricyclic levels due to less potential GYP interactions. By expert consensus, second- (venlafaxine) and third-line (nefazadone and gabapentin) agents may be used when clinical response is inadequate despite a lack of controlled data. Venlafaxine may be substituted for a more typical SSRI while nefazadone or gabapentin may be added to either clomipramine or a SSRI. The combination of venlafaxine with other SSRIs is not generally recommended as it may increase the risk of a serotonin syndrome. The addition of nefazadone to SSRIs presents a lesser risk. 

Other concerns of particular relevance to children and adolescents are due to pharmacokinetic differences between them and adults. Although clomipramine is the... 

Gex-Fabry M, Balant-Gorgia AE, Balant LP, Gar-rone G. Clomipramine metabolism. Model-based analysis of variability factors from drug monitoring data. Clin Pharmacokinet 1990 19 241-55. 

Clomipramine, fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram are extensively metabolized in the Liver, and patients with significant liver disease should be prescribed these drugs cautiously and in lower doses than those used in healthy subjects. The pharmacokinetics of fluoxetine and fluvoxamine were similar in patients with renal faUme and in healthy subjects however, the manufacturer recommends starting with a lower dose in patients with renal impairment. The pharmacokinetics of sertraline are not altered in patients with significant renal dysfunction, and dosage adjustment is not necessary in these patients. Increased plasma concentrations of paroxetine occur in subjects with renal impairment. The initial dose of paroxetine should be reduced in patients with severe renal impairment, and upward titration should occm more slowly. No dosage adjustment is necessary for patients with mild to moderate renal impairment receiving citalopram. 

Clomipramine is rapidly absorbed following oral administration. Maximum plasma concentrations occur within 2 hours. It is highly protein-bound (>90%) in the blood and has a half-life of 19 to 37 hours.The drug is metabolized to desmethylclomipramine, which is pharmacologically active. The pharmacokinetics of the SSRIs are discussed in Chapter 67. 

Oshima, N. Kotaki, H. Sawada, Y. Iga, T. Tissue distribution of amitriptyline after repeated administration in rats. Drug Metab.Dispos., 1994,22, 21-25 [rat plasma liver kidney lung brain muscle heart extracted nortriptyline clomipramine is IS column temp 35 LOQ 10 n mL pharmacokinetics]... 

Jurima-Romet, M. Crawford, K. Cyr, T. Inaba, T. Terfenadine metabolism in human liver. In vitro inhibition by macrolide antibiotics and azole antifungals. Drug Metab.Dispos., 1994, 22, 849—857 [extracted metabolites microsomal incubations rat column temp 35 LOQ 92 nM] von Moltke, L.L. Greenblatt, D.J. Duan, S.X. Harmatz, J.S. Shader, R.I. In vitro prediction of the terfenadine-ketoconazole pharmacokinetic interaction. J.Clin.Pharmacol., 1994, 34, 1222—1227 [clomipramine (IS) microsomal incubations]... 

Table 21.9. Pharmacokinetics of the Tricyclic Nonselective Reuptake Inhibit) Parameters Amitripytline Clomipramine Doxepin Imipramine Trim...

No pharmacokinetic interaction occurs between imipramine or mirtazapine and olanzapine, but the additive effects of clomipramine and olanzapine was thought to have caused a seizure in one patient. 

Clomipramine serum levels were reported to be increased by mo-dallnil in one patient. However, a study found no pharmacokinetic interaction. 

John VA, Luscombe DK, Kemp H. Effects of age, cigarette smoking and the oral contraceptive on the pharmacokinetics of clomipramine and its desmethyl metabolite during chronic dosing. 

Orlistat appears not to affect the plasma levels of clomipramine or desipramine in patients, or the pharmacokinetics of amitriptyline in healthy subjects. 

A preliminary study in patients who had been taking psychotropic drugs long-term found no clinically relevant changes in plasma levels of clomipramine (3 patients) or desipramine (1 patient) when they were given orlistat over an 8-week period. A study in 20 healthy subjects found that orlistat 120 mg three times daily for 6 days did not affect the pharmacokinetics of amitriptyline 25 mg three times daily. ... 

A number of other reports and studies clearly confirm that marked increases occur in the levels of amitriptyline, " clomipramine, desipramine, " imipramine " and nortriptyline, " accompanied by toxicity, if fluoxetine is added without reducing the dosage of the tricyclic antidepressant. Delirium and seizures have also been described, and a death has been attributed to chronic amitriptyline toxicity caused by fluoxetine. The pharmacokinetics of fluoxetine appear not to be affected by amitriptyline. ... 

Haffen E, Vandel P, Bonin B, Vandel S. Citalopram pharmacokinetic interaction with clomipramine. UDP-glucurono ltransferase inhibition A case report Therapie (1999) 54, 768-70. 

Amitriptyline and nortriptyline plasma levels can be increased by sodium valproate and valpromide, but in contrast, an isolated report attributes a paradoxical rise in serum desipramine levels to the withdrawal of valproic acid. Valproate pharmacokinetics may be moderately affected by amitriptyline. Status epilepticus has been attributed to elevated clomipramine levels in a patient taking valproic acid. 

Measurement of Clomipramine, N-Des-methylclomipramine, Imipramine, and Dehydroimipramine in Biological Fluids by Selective Ion Monitoring and Pharmacokinetics of Clomipramine... 

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