Electrophysiological Effects of the Anti‐Cancer Drug Lapatinib on Cardiac Repolarization

• Published in: Basic & clinical pharmacology & toxicology Vol. 107; no. 1; pp. 614 - 618
• Main Authors: Lee, Hyang‐Ae, Kim, Eun‐Joo, Hyun, Sung‐Ae, Park, Sung‐Gurl, Kim, Ki‐Suk
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.07.2010; Blackwell
• Subjects: Action Potentials - drug effects; Animals; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Line; Dose-Response Relationship, Drug; Ether-A-Go-Go Potassium Channels - drug effects; Ether-A-Go-Go Potassium Channels - metabolism; Heart Conduction System - drug effects; Humans; Ion Channels - drug effects; Ion Channels - metabolism; KCNQ1 Potassium Channel - drug effects; KCNQ1 Potassium Channel - metabolism; Kidney - cytology; Kidney - embryology; Kidney - metabolism; Medical sciences; Muscle Proteins - drug effects; Muscle Proteins - metabolism; NAV1.5 Voltage-Gated Sodium Channel; Patch-Clamp Techniques; Pharmacology. Drug treatments; Potassium Channels, Inwardly Rectifying - drug effects; Potassium Channels, Inwardly Rectifying - metabolism; Potassium Channels, Voltage-Gated - drug effects; Potassium Channels, Voltage-Gated - metabolism; Purkinje Fibers - drug effects; Purkinje Fibers - physiopathology; Quinazolines - pharmacology; Rabbits; Sodium Channels - drug effects; Sodium Channels - metabolism; Transfection; Antineoplastic agent; Heart; Drug; Repolarization; Enzyme; Tyrosine kinase inhibitor; Transferases; Enzyme inhibitor; Electrophysiology; Circulatory system; Lapatinib; Protein-tyrosine kinase
• ISSN: 1742-7835; 1742-7843
• DOI: 10.1111/j.1742-7843.2010.00556.x

:  Lapatinib is one of several tyrosine kinase inhibitors used against solid tumour cancers such as breast and lung cancer. Although lapatinib is associated with a risk of QT prolongation, the effects of the drug on cellular cardiac electrical properties and on action potential duration (APD) have not been studied. To evaluate the potential effects of lapatinib on cardiac repolarization, we investigated its electrophysiological effects using a whole‐cell patch–clamp technique in transiently transfected HEK293 cells expressing human ether‐à‐go‐go (hERG; to examine the rapidly activating delayed rectifier K+ current, IKr), KCNQ1/KCNE1 (to examine the slowly activating delayed rectifier K+ current, IKs), KCNJ2 (to examine the inwardly rectifying K+ current, IK1), or SCN5A (to examine the inward Na+ current, INa) and in rat cardiac myocytes (to examine the inward Ca2+ current, ICa). We also examined its effects on the APD at 90% (APD90) in isolated rabbit Purkinje fibres. In ion channel studies, lapatinib inhibited the hERG current in a concentration‐dependent manner, with a half‐maximum inhibition concentration (IC50) of 0.8 ± 0.09 μm. In contrast, at concentrations up to 3 μm, lapatinib did not significantly reduce the INa, IK1 or ICa amplitudes; at 3 μm, it did slightly inhibit the IKs amplitude (by 19.4 ± 4.7%; p < 0.05). At 5 μm, lapatinib induced prolongation of APD90 by 16.1% (p < 0.05). These results suggest that the APD90‐prolonging effect of lapatinib on rabbit Purkinje fibres is primarily a result of inhibition of the hERG current and IKs, but not INa, IK1 or ICa.