Preclinical Research Unit, Sumitomo Dainippon Pharma Co., Ltd.
Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School.
J Toxicol Sci. 2019;44(7):441-457. doi: 10.2131/jts.44.441.
The objective of this study is to assess the response of telemetered common marmosets to multiple cardiac ion channel inhibitors and to clarify the usefulness of this animal model in evaluating the effects of drug candidates on electrocardiogram (ECG). Six multiple cardiac ion channel inhibitors (sotalol, astemizole, flecainide, quinidine, verapamil and terfenadine) were orally administered to telemetered common marmosets and changes in QTc, PR interval and QRS duration were evaluated. Drugs plasma levels were determined to compare the sensitivity in common marmosets to that in humans. QTc prolongation was observed in the marmosets dosed with sotalol, astemizole, flecainide, quinidine, verapamil and terfenadine. PR prolongation was noted after flecainide and verapamil administration, and QRS widening occurred following treatment with flecainide and quinidine. Drugs plasma levels associated with ECG changes in marmosets were similar to those in humans, except for verapamil-induced QTc prolongation. Verapamil-induced change is suggested due to body temperature decrease. These results indicate that telemetered common marmoset is a useful animal for evaluation of the ECG effects of multiple cardiac ion channel inhibitors and the influence of body temperature change should be considered in the assessment.
本研究旨在评估遥测普通狨猴对多种心脏离子通道抑制剂的反应，并阐明该动物模型在评估候选药物对心电图（ECG）影响方面的有用性。将六种多种心脏离子通道抑制剂（索他洛尔、阿司咪唑、氟卡尼、奎尼丁、维拉帕米和特非那定）口服给予遥测普通狨猴，并评估 QTc、PR 间隔和 QRS 持续时间的变化。测定药物的血浆水平，以比较普通狨猴与人类的敏感性。在给予索他洛尔、阿司咪唑、氟卡尼、奎尼丁、维拉帕米和特非那定的狨猴中观察到 QTc 延长。给予氟卡尼和维拉帕米后出现 PR 延长，给予氟卡尼和奎尼丁后 QRS 增宽。与普通狨猴心电图变化相关的药物血浆水平与人类相似，除了维拉帕米引起的 QTc 延长。维拉帕米引起的变化可能是由于体温下降所致。这些结果表明，遥测普通狨猴是评估多种心脏离子通道抑制剂对心电图影响的有用动物模型，在评估中应考虑体温变化的影响。
