Department of Pharmacology, Toho University Graduate School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.
Department of Pharmacology, Toho University Graduate School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan; Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.
J Pharmacol Sci. 2018 Jun;137(2):237-240. doi: 10.1016/j.jphs.2018.06.005. Epub 2018 Jun 18.
We analyzed torsadogenic and pharmacokinetic profile of E-4031 using chronic atrioventricular block dogs. E-4031 in intravenous doses of 0.03, 0.1 and 0.3 mg/kg over 10 min prolonged QT/QTc, and increased short-term variability of QT in a dose-related manner (n = 4), resulting in onset of torsade de pointes in 1 animal after the middle dose and 4 animals after the high dose, while it attained peak plasma concentrations of 16.5, 60.5 and 182.5 ng/mL at 10 min after their start of administration, respectively (n = 2). These results bridge the gap of information between in vitro proarrhythmia assay and clinical observation in human subjects.
我们使用慢性房室传导阻滞犬分析 E-4031 的致扭转型和药代动力学特征。E-4031 以 0.03、0.1 和 0.3 mg/kg 的静脉剂量输注 10 分钟，剂量相关地延长 QT/QTc 间期，并增加 QT 间期短期变异性（n=4），导致 1 只动物在中剂量后和 4 只动物在高剂量后出现尖端扭转型室性心动过速，而在给药后 10 分钟时，其达到的峰值血浆浓度分别为 16.5、60.5 和 182.5 ng/mL（n=2）。这些结果填补了体外致心律失常试验和人体临床观察之间的信息空白。
