Hanada Erika, Ohtani Hisakazu, Hirota Michiko, Uemura Noriko, Nakaya Haruaki, Kotaki Hajime, Sato Hitoshi, Yamada Yasuhiko, Iga Tatsuji
Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
J Pharm Pharmacol. 2003 Jul;55(7):995-1002. doi: 10.1211/0022357021459.
Disopyramide, a class Ia antiarrhythmic agent, has been reported to induce torsades de pointes (TdP) associated with excessive QT prolongation in electrocardiogram (ECG), especially when concomitantly administered with erythromycin, a macrolide antibiotic agent. In this study, we have evaluated the effects of erythromycin on action potential duration (APD) and potassium currents in rat ventricular myocytes in comparison with disopyramide. We have evaluated the relationship between in-vitro potassium current inhibition and in-vivo QT prolongation observed in a previous study. Action potentials and membrane potassium currents, including delayed rectifier current (I(K)) and transient outward current (I(to)), were recorded using a whole-cell patch clamp method in enzymatically-dissociated ventricular cells. Erythromycin and disopyramide prolonged APD in a concentration-dependent manner. Disopyramide (10-100 microM) and erythromycin (100 microM) led to increases in the APD at 90% repolarization level. Disopyramide reduced I(K) (IC50 = 37.2 +/- 0.17 microM) and I(to) (IC50 = 20.9 +/- 0.13 microM) while erythromycin reduced I(K) (IC50 = 60.1 +/- 0.29 microM) but not I(to). The observed prolongation of APD might be ascribed to the inhibition of potassium currents. Erythromycin produced the prolongation of APD and the inhibition of potassium currents with a lag time after addition of the drugs, which suggested that erythromycin might not reach potassium channels from outside the ventricular cells. The potency of disopyramide was almost equivalent under in-vitro and in-vivo conditions. However, potency of erythromycin in-vitro was far weaker than that in-vivo reported in a previous study, presumably due to a difference in the uptake of erythromycin into ventricular myocytes between in-vivo and in-vitro conditions. Therefore, when drug-induced risks of QT prolongation are to be evaluated, the difference of potencies between in-vitro and in-vivo should be taken into consideration.
丙吡胺是一种Ia类抗心律失常药物，据报道，它会诱发与心电图（ECG）QT间期过度延长相关的尖端扭转型室性心动过速（TdP），尤其是在与大环内酯类抗生素红霉素联合使用时。在本研究中，我们评估了红霉素与丙吡胺相比，对大鼠心室肌细胞动作电位时程（APD）和钾电流的影响。我们还评估了在之前的一项研究中观察到的体外钾电流抑制与体内QT间期延长之间的关系。使用全细胞膜片钳方法，在酶解的心室细胞中记录动作电位和膜钾电流，包括延迟整流电流（I(K)）和瞬时外向电流（I(to)）。红霉素和丙吡胺以浓度依赖性方式延长APD。丙吡胺（10 - 100 microM）和红霉素（100 microM）导致90%复极化水平时的APD增加。丙吡胺降低I(K)（IC50 = 37.2 +/- 0.17 microM）和I(to)（IC50 = 20.9 +/- 0.13 microM），而红霉素降低I(K)（IC50 = 60.1 +/- 0.29 microM）但不降低I(to)。观察到的APD延长可能归因于钾电流的抑制。红霉素在添加药物后有延迟时间才产生APD延长和钾电流抑制，这表明红霉素可能无法从心室细胞外部到达钾通道。丙吡胺在体外和体内条件下的效力几乎相当。然而，红霉素在体外的效力远弱于之前一项研究中报道的体内效力，这可能是由于体内和体外条件下心室肌细胞对红霉素摄取的差异。因此，在评估药物诱发QT间期延长的风险时，应考虑体外和体内效力的差异。
