Mechanisms of gefitinib-induced QT prolongation

• Published in: European journal of pharmacology Vol. 910; p. 174441
• Main Authors: Jie, Ling-Jun, Li, Yun-Da, Zhang, He-Qiang, Mao, Liang, Xie, Hua-Bin, Zhou, Fa-Guang, Zhou, Tian-Li, Xie, Dong, Lin, Jia-Le, Li, Gui-Yang, Cai, Bin-Ni, Zhang, Yan-Hui, Wang, Yan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.11.2021
• Subjects: Action potential; Action Potentials - drug effects; Animals; Corrected QT interval; Electrocardiography - drug effects; ERG1 Potassium Channel - antagonists & inhibitors; ERG1 Potassium Channel - metabolism; Gefitinib; Gefitinib - pharmacology; Guinea Pigs; Heart Ventricles - drug effects; HEK293 Cells; Human ether-à-go-go-related gene potassium channel; Humans; Long QT Syndrome - chemically induced; Long QT Syndrome - metabolism; Male; Myocardial Contraction - drug effects; Myocytes, Cardiac - drug effects; Patch-Clamp Techniques; Potassium Channel Blockers - pharmacology; Corrected QT interval; Action potential; Gefitinib; Human ether-à-go-go-related gene potassium channel
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2021.174441

Gefitinib, a tyrosine kinase inhibitor, was the first targeted therapy for non-small cell lung cancer (NSCLC). Gefitinib could block human Ether-à-go-go-Related Gene (hERG) channel, an important target in drug-induced long QT syndrome. However, it is unclear whether gefitinib could induce QT interval prolongation. Here, whole-cell patch-clamp technique was used for evaluating the effect of gefitinib on rapidly-activating delayed rectifier K+ current (IKr), slowly-activating delayed rectifier K+ current (IKs), transient outward potassium current (Ito), inward rectifier K+ current (IK1) and on action potentials in guinea pig ventricular myocytes. The Langendorff heart perfusion technique was used to determine drug effect on the ECG. Gefitinib depressed IKr by binding to open and closed hERG channels in a concentration-dependent way (IC50: 1.91 μM). The inhibitory effect of gefitinib on wildtype hERG channels was reduced at the hERG mutants Y652A, S636A, F656V and S631A (IC50: 8.51, 13.97, 18.86, 32.99 μM), indicating that gefitinib is a pore inhibitor of hERG channels. In addition, gefitinib accelerated hERG channel inactivation and decreased channel steady-state inactivation. Gefitinib also decreased IKs with IC50 of 23.8 μM. Moreover, gefitinib increased action potential duration (APD) in guinea pig ventricular myocytes and the corrected QT interval (QTc) in isolated perfused guinea pig hearts in a concentration-dependent way (1–30 μM). These findings indicate that gefitinib could prolong QTc interval by potently blocking hERG channel, modulating kinetic properties of hERG channel. Partial block of KCNQ1/KCNE1 could also contribute to delayed repolarization and prolonged QT interval. Thus, caution should be taken when gefitinib is used for NSCLC treatment. •Gefitinib decreased hERG currents by binding to open and closed hERG channels in a concentration-dependent way.•S636, S631, F656 and Y652 are key molecular determinants of gefitinib blockade of hERG channels.•Gefitinib accelerated hERG channel inactivation and decreased channel steady-state inactivation.•Gefitinib partially inhibited KCNQ1/KCNE1 currents.•Gefitinib prolongs QTc interval in isolated perfused guinea pig hearts in a concentration-dependent way.