Amisulpride has no effect on plasma clozapine concentrations.

To the Editors: To date, only a few systematic studies analyzing the use of combinations of antipsychotics have been undertaken. However, knowing how clozapine and amisulpride interact could be particularly important as patients with schizophrenia might well profit from such a combination treatment; indeed, a few case reports and studies support this notion. Good efficacy and tolerability of this combination in treating positive and negative symptoms have been reported even when the disease has previously been retractable to treatment. The efficacy of the drug combination can be attributed to the complementary receptor profiles of the two drugs. The atypical antipsychotic drug amisulpride is a benzamide derivative that selectively blocks the dopamine D2 and D3 receptors with no affinity for any other known receptor. It preferentially blocks mesolimbic, rather than nigrostriatal dopaminergic transmission, and the dopamine D2 autoreceptors, rather than the postsynaptic receptors; the dopamine D3 receptors are antagonized preferentially in the limbic areas. The efficacy of amisulpride was confirmed in several studies for both positive and negative symptoms of schizophrenia. Amisulpride is rapidly resorbed after oral intake and the plasma concentrations reach a maximum twice, once after 1 hour and again after 3 to 4 hours. The first-pass metabolism of amisulpride is low; after oral intake the bioavailability is 48%. Seventeen percent of amisulpride binds to plasma proteins. Its elimination halftime is about 12 hours and steady state is achieved after about 2 to 3 days. Amisulpride is mainly eliminated via the kidneys. After intravenous administration, 75% of the dose can be detected in urine. Furthermore, about 90% of amisulpride in the urine was found to be unmetabolized, unbound drug. After a one-time oral intake of amisulpride, only 24% to 47% of the oral dose was found in urine and, of this, 96% had not been altered metabolically. There are no active metabolites; after oral administration, only a minor portion of drug undergoes metabolism by hydroxylation, N-dealkylation, and oxidation of the tetrahydropyrrol core via the cytochrome P-450 system. However, 2 inactive metabolites have been identified and found in urine; they correspond to about 4% of the administered dose of amisulpride. A far greater percentage of amisulpride is excreted unchanged: about 75% via the kidneys and about 20% via the feces. There is a linear relationship between the dose and plasma concentration of amisulpride. As amisulpride is mainly eliminated via the kidneys, the dose of amisulpride has to be corrected if creatinine clearance is restricted. Only little is known about how the interaction with other medications affects the pharmacokinetics of amisulpride. The tricyclic dibenzodiazepine clozapine is a strong D4 receptor antagonist. Furthermore, it has a slight antagonistic effect on D1, D2, D3, and D5 receptors and possesses anticholinergic, antihistaminergic, antiserotonergic, and anti-a-adrenergic properties. The pharmacokinetics of clozapine is subject to numerous influencing variables. About 95% of orally administered clozapine is absorbed, that is, almost all of it. After about 1 to 4 hours, the maximum plasma concentration is achieved. Clozapine has a low first-pass metabolism, with a bioavailability of about 50% to 60%. About 95% of the substance bind to plasma proteins. The elimination half-time is about 14 hours (6–26 hours) and steady state is not achieved until after about 6 to 10 days. Clozapine is almost completely metabolized in the liver by the cytochrome P-450 isoenzymes CYP 1A2 and CYP 3A4 before it is eliminated. To a minor degree, CYP 2D6 and CYP 2C19 are also involved in clozapine metabolism. Four metabolites are known; among these only N-desmethylclozapine is pharmacologically active. About 50% of the orally administered dose are eliminated in metabolized form in the urine and about 30% in the feces. It is known that plasma concentrations of clozapine are affected by a variety of medications. It is also known, however, that clozapine affects the plasma concentrations of other compounds as well. We have demonstrated that clozapine increases the plasma concentration of amisulpride. Based on the findings that plasma concentrations of amisulpride were higher in patients who were treated with both clozapine and amisulpride than in patients receiving amisulpride monotherapy, a longitudinal study was conducted in 5 patients who received comedication with clozapine in addition to amisulpride; in all patients clozapine comedication increased the plasma concentrations of amisulpride, with an average increase of 62%. We assumed that amisulpride is actively secreted via the renal transport system, in particular, via cation-proton-antiporters. The effect of clozapine on amisulpride that we observed can most likely be attributed to competitive effects on this transport system. Presumably, both of the main metabolites, clozapine-Noxide and N-desmethylclozapine, are secreted via the renal tubules by cationic-proton-antiporters, whereby these metabolites are considerably better substrates than the parent compound. We thus assumed that the clozapine metabolites in particular compete with amisulpride for binding at the renal transport system. Our assumption that amisulpride is actively secreted and that other organic cations interfere with the transport process is supported by previous data of Kamizono et al, who showed in rat studies that renal clearance of sultopride, a deaminated derivative of amisulpride, is significantly decreased by procainamide. Because a combined clozapineamisulpride medication may offer therapeutic advantages, it would be very interesting to learn whether the administration of amisulpride, in addition to