Sustained QT prolongation induced by tacrolimus in guinea pigs

Recently, clinical cases have been reported of QT prolongation and torsades de pointes associated with the use of tacrolimus (FK506). We examined the relationship between QTc prolongation and the pharmacokinetics of FK506 in guinea pigs in order to evaluate the arrhythmogenicity of FK506 in comparis on with quinidine (QND). FK506 (0.1 or 0.01 mg/hr/kg) or QND (30 mg/hr/kg) was intravenously infused to guinea pigs and time profiles of drug concentr ation in blood and QTc interval were examined during and after infusion. Bo th FK506 and QND evoked a significant QTc prolongation, and the dose-respon se relationship showed an anti-clockwise hysteresis, FK506-induced QTc prol ongation persisted throughout the duration of the experiment despite a decl ine in the plasma FK506 concentration, whilst QND-induced QTc prolongation disappeared as plasma concentrations decreased. FK506 induced a sustained Q Tc prolongation in guinea pigs at drug concentrations in blood that corresp ond to its therapeutic range in human, suggesting that it might be of clini cal significance to monitor the electrocardiogram, especially when patients have congenital or acquired QT-prolonging risk factors. (C) 1999 Elsevier Science Inc.