Lengthening of Cardiac Repolarization in Isolated Guinea Pigs Hearts by Sequential or Concomitant Administration of Two IKr Blockers

Block of IKr is of major concern in drug safety. The objective of this study was to assess prolongation of cardiac repolarization during the combined use of two IKr blockers when administered concomitantly or sequentially. (1) When isolated hearts from male guinea pigs were perfused concomitantly with two IKr blockers, prolongation of monophasic action potential duration measured at 90% (MAPD90) was less than the summation of effects observed for each drug perfused alone. (2) In sequential administration, when ketoconazole or erythromycin was perfused first, they antagonized MAPD90-prolonging effects of domperidone. This effect was absent when domperidone or dofetilide was perfused first. Patch-clamp experiments confirmed that the order of sequential perfusion impacts the decrease in HERG tail amplitude. In conclusion, this study does not support the concept that potentiation of drug effects is observed during the combined administration of two IKr blockers. Furthermore, order of administration of two IKr blockers together may be an important factor in drug-induced long QT syndrome.