Clinical Pharmacokinetics of Clomipramine

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Abstract
Clomipramine is a tricyclic antidepressant medication widely used in Western Europe. Its pharmacokinetics have been studied essentially in healthy volunteers. By combining published information obtained during observational studies, it has been possible to derive a fairly precise picture of the behaviour of both parent compound and main metabolite (demethyl-clomipramine) in humans. Clomipramine can be compared with amitriptyline or imipramine so far as its physicochemical properties are concerned. As a consequence, its pharmacokinetic profile is also similar to that observed for these 2 drugs. Clomipramine is well absorbed from the gastrointestinal tract, but undergoes an important first-pass metabolism to demethyl-clomipramine which is pharmacologically active and participates in both therapeutic and unwanted effects. Protein binding is high, and the apparent volume of distribution is very large (i.e. < 1000L). After reaching the systemic circulation, clomipramine is further biotransformed into demethyl-clomipramine, and both active principles are hydroxylated to metabolites which are further conjugated before being excreted in urine. Hydroxylation of parent drug and metabolite is under polymorphic genetic control by the same cytochrome P450 as debrisoquine and sparteine. The apparent elimination half-life of clomipramine is about 24h and that of demethyl-clomipramine, 96h. Accordingly, the time to reach steady-state for both active moieties is in general around 3 weeks. Various pathological or environmental factors influence the behaviour of clomipramine and demethyl-clomipramine. Patients genetically deficient in hydroxylation accumulate demethylclomipramine at high concentrations that can produce serious side effects and/or nonresponse. The same is true for the coadministration of neuroleptics, in particular phenothiazines. Smoking induces demethylation, whereas long term alcohol intake appears to reduce this metabolic pathway. Finally, age usually diminishes both demethylation and hydroxylation, leading to a lower daily dose of clomipramine in most elderly patients. Studies relating blood concentrations of clomipramine and demethyl-clomipramine are conflicting. However, analysis of the available information indicates that blood concentrations lower than 150 µg/L are usually associated with nonresponse, whereas those above 450 µg/L seldom lead to an improvement in the efficacy of therapy. As a consequence clomipramine, like the other tricyclics, is an antidepressant with a fairly narrow therapeutic range. This property, combined with a high interindividual variability, makes this class of drugs ideal candidates for blood concentration monitoring.