Sertindole metabolism

Cyt 2D6 metabolizes haloperidol, risperidone, thioridazine, sertindole, olanzapine and clozapine common substrates - fluoxetine, paroxetine, sertraline, venlafaxine, amitriptyline, clomipramine, desipramine, imipramine, nortriptyline, propranolol, metoprolol, timolol, codeine, encainide, flecanide. Common inhibitors - paroxetine, sertraline, fluoxetine. 

Cyt 3A3/4 metabolizes clozapine, sertindole, quetiapine common substrates -tricyclic antidepressants, nefazodone, sertraline, carbamazepine, ethosuximide, terfenadine, benzodiazepines, diltiazem, nifedipine, verapamil, erythromycin, cyclosporine, lidocaine, quinidine, cisapride, paracetamol. Common inhibitors -nefazodone, fluvoxamine, fluoxetine, ketoconazole. 

FLECAINIDE ANTIPSYCHOTICS -PHENOTHIAZINES, AMISULPRIDE, PIMOZIDE, SERTINDOLE Risk of arrhythmias Additive effect. Also, haloperidol and thioridazine inhibit CYP2D6-mediated metabolism of flecainide Avoid co-administration... 

CALCIUM CHANNEL BLOCKERS SERTINDOLE Plasma concentrations of sertindole are t by diltiazem and verapamil Diltiazem and verapamil inhibit CYP3A4-mediated metabolism of sertindole Avoid co-administration raised sertindole concentrations are associated with an t risk of prolonged Q-T interval and therefore ventricular arrhythmias, particularly torsades de pointes... 

ANTIPSYCHOTICS CARBAMAZEPINE, PHENYTOIN, PHENOBARBITAL, PRIMIDONE 1 levels of apiprazole (all), haloperidol (carbamazepine, phenobarbital), clozapine, quetiapine, sertindole (carbamazepine, phenytoin), risperidone and olanzapine (carbamazepine) Induction of metabolism Watch for poor response to these antipsychotics, and consider increasing the dose... 

ARIPIPRAZOLE, HALOPERIDOL, CLOZAPINE, PIMOZIDE, RISPERIDONE, SERTINDOLE PROTEASE INHIBITORS Possibly T levels of antipsychotic Inhibition of CYP3A4- and/or CYP2D6-mediated metabolism Avoid co-administration of clozapine with ritonavir, and pimozide or sertindole with protease inhibitors. Use other antipsychotics with caution as 1 dose may be required with risperidone, watch closely for extrapyramidal side-effects and neuroepileptic malignant syndrome... 

Sertindole 30 mg/day had no effects on the pharmacokinetics of a single dose of terfenadine 120 mg or of its metabolite (11). The authors concluded that sertindole at this dose does not inhibit the metabolism of terfenadine. 

ARIPIPRAZOLE, CLOZAPINE, HALOPERIDOL, PERPHENAZINE, RISPERIDONE, SERTINDOLE SSRIs Possible t plasma concentrations of these antipsychotics Inhibition of CYP2D6-mediated metabolism of these drugs. The clinical significance of this depends upon whether alternative pathways of metabolism of these substrates are also inhibited by co-adminis-tered drugs. The risk is theoretically greater with clozapine, haloperidol and olanzapine because their CYPl A2-mediated metabolism Is also Inhibited by SSRIs Warn patients to report T side-effects of these drugs, and consider reducing the dose of the antipsychotic... 

The metabolism of sertindole is markedly increased by enzyme inducers, such as phenytoin and carbamazepine, and plasma sertindole levels may be reduced by 2 to 3-fold. The manufacturers therefore say that the daily dosage of sertindole may need to be increased towards the upper end of the maximum dosage range to accommodate this interaction. ... 

Studies in patients found that diltiazem, nifedipine or verapamil resulted in a 20% reduction in the sertindole elearanee, attributed to inhibition of CYP3A metabolism. The manufaeturers contraindieate concurrent use (diltiazem and verapamil are specifically named) as raised sertindole levels may prolong the QT interval. ... 

A single 120-mg dose of terfenadine was given to 14 healthy subjects who had taken sertindole 20 mg daily for 5 days. The pharmacokinetics of neither drug was significantly changed, nor that of the metabolite of terfenadine (carboxyterfenadine), although it was concluded that sertindole may be a modest inhibitor of the first pass metabolism of terfenadine. However, it was foimd that the combination caused an additive increase of 49 milliseconds in the QTc interval and therefore these two drugs are contraindicated by the manufacturer. ... 

De Hert M, Mittoux A, He Y, Peuskens J. Metabolic parameters in the short- and long-term treatment of schizophrenia with sertindole or risperidone. Eur Arch Psychiatry Clin Neurosci 2011 261 231-9. 

Cardiovascular The addition of sertindole to clozapine as an augmentation strategy showed no additional benefit and four patients experienced an exacerbation of psychosis (two required hospitalisation) [276 -]. Metabolic parameters did not change but QTc was prolonged compared to placebo. 

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