Pharmacodynamic analysis of the electrocardiographic interaction between disopyramide and erythromycin in rats

Disopyramide (DP) is known to induce QT prolongation and Torsades de Pointe s (TdP) when administered concomitantly with erythromycin (EM). To define a nd evaluate quantitatively the arrhythmogenic risk of the concomitant admin istration of DP and EM, we investigated the influence of EM on the pharmaco kinetics and pharmacodynamics of DP in rats. The time profiles of change in QT interval and plasma concentration of each drug were evaluated during an d after constant intravenous infusion of DP (6.0 or 15.0 mg/kg/h), EM (4.0 or 8.0 mg/kg/h), and coadministration of DP and EM (DP 6.0 mg/kg/h plus EM 4.0 mg/kg/h). Each agent induced QT prolongation at plasma concentrations w ithin the therapeutic range in humans. DP-induced QT prolongation was propo rtional to its plasma concentration. In the case of EM, the E-max model wit h an "effect compartment" could explain the relationship between plasma EM concentrations and changes in QT interval. Although coadministration of EM with DP gave enhanced QT prolongation compared to dosing with DP alone, EM did not affect the pharmacokinetics of DP. In conclusion, it was shown that a pharmacodynamic interaction contributes to the electrocardiographic adve rse reaction (i.e., QT prolongation) induced by coadministration of DP and EM in rats.