¹Universiteé de Montreéal, Montreal, PQM, Canada

Abstract

Background/aims: Block of I_Krcauses significant lengthening of cardiac repolarization and is of major concern for drug safety. The objective of the present study was to assess prolongation of cardiac repolarization during the combined use of two I_Kr blockers when administered sequentially in different orders.

Methods: Hearts (n=84) from Hartley male guinea-pigs were isolated and buffer-perfused in the Langendorff mode. Monophasic action potential duration was measured at 90% repolarization (MAPD₉₀). After a 5 min perfusion with buffer, hearts were perfused with[domperidone (50, 150 and 300 nM) followed by erythromycin (10 M) or by ketoconazole (10 M)], or inversely with[ketoconazole administered first (10 M) followed by domperidone (50, 150 and 300 nM)].

Results: Increasing concentrations of domperidone caused a concentration-dependent prolongation of MAPD₉₀. Sequential administration of erythromycin or ketoconazole caused an additive effect. In contrast, MAPD₉₀ prolongation caused by domperidone was no longer concentration-dependent when ketoconazole was administered first.

Conclusion: Our results demonstrate that the order of the sequential administration of two I_Kr blockers seems to be an important factor on lengthening of cardiac repolarization. Further studies are necessary to elucidate the responsible mechanism.