Terfenadine Sertindole

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. 

The most common mechanism of dysrhythmias at the molecular level is by inhibition of the potassium channels known as IK, which are encoded by the human ether-a-go-go-related gene (HERG). The antidysrhythmic drugs that affect these channels include almokalant, amiodar-one, azimilide, bretylium, dofetilide, ibutilide, sematilide, D-sotalol, and tedisamil (all drugs with Class III actions) and bepridil, disopyramide, prenylamine, procainamide, propafenone, quinidine, and terodiline (all drugs with Qass I actions). Other drugs that affect these channels but are not used to treat cardiac dysrhythmias include astemizole and terfenadine (antihistamines), cisapride, erythromycin, haloperidol, sertindole, and thioridazine. 

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. 

Wong SL, Cao G, Mack R, Granneman GR. Lack of CYP3A inhibition effects of sertindole on terfenadine in healthy volunteers. Int J Chn Pharmacol Ther 1998 36(3) 146-51. 

Terfenadine/Seldane (antihistamine, February 1998), Cisapride/Propulsid (GI prokinetic, July 2000), Grepafloxacin/Raxar (antibiotic, November 1999), Sertindole (antipsychotic, December 1998), and As-temizole (antihistamine, June 1999). See Table 1 for a list of nonantiarrhythmic drugs associated with QT interval prolongation. 

K41.1 (ergl) KCNH2 7q35-36 minK, MiRPl Brain, heart, kidney, liver, lung, ovary, pancreas, testis, prostate, uterus, small intestine Astemizole, BeKM-1, ergtoxin, sertindole, dofetilide, cisapride, pimozide, terfenadine, halofantrine, BRL32872, E-4031, CT haloperidol, imipramine, cocaine, ketoconazole None... 

The manufacturers of sertindole contraindicate the concurrent use of cimetidine, diltiazem, erythromycin, itraconazole, ketoco-nazole, terfenadine and verapamil because of an increased risk of cardiac arrhythmias. Carbamazepine and phenytoin reduce plasma sertindole levels whereas fluoxetine and paroxetine increase them. No clinically relevant interactions occur with alprazolam, antacids, food or tobacco smoking. 

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. ... 

Granneman GR, Wozniak P, Ereshefsky L, Silber C, Mack R, Effect of sertindole on the pharmacokinetics of terfenadine (M94-146). Poster presentation at the American College of Neuropsychopharmacology Annual Meeting, San Juan, Puerto Rico, December 1996. 

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