Comparative Pharmacology of Guinea Pig Cardiac Myocyte and Cloned hERG (I_Kr) Channel

Abstract

Our study demonstrates the advantages of cardiac myocytes over heterologously expressed hERG channels in predicting QT interval prolongation and TdP in man. The potencies of some drugs in cardiac myocytes were similar to hERG, but only myocytes were able to detect important changes in APD characteristics and display EADs predictive of arrhythmia development. We observed similar qualitative drug profiles in cardiac myocytes, dog Purkinje fibers, and animal and human telemetry studies. Therefore, isolated native cardiac myocytes are a better predictor of drug-induced QT prolongation and TdP than heterologously expressed hERG channels. Isolated cardiac myocytes, when used with high-throughput patch clamp instruments, may have an important role in screening potential cardiotoxic compounds in the early phase of drug discovery. This would significantly reduce the attrition rate of drugs entering preclinical and/or clinical development. The current kinetics and amplitudes of the cloned hERG channel were profoundly affected by temperature, significantly altering the potency of one drug (E-4031). This finding cautions against routine drug testing at room temperature compared to physiologic temperature when using the cloned hERG channel.

Comparative Evaluation of HERG Currents and QT Intervals following Challenge with Suspected Torsadogenic and Nontorsadogenic Drugs

“…Because loratadine also showed some use-dependent ability to block I HERG at micromolar concentrations, and because there are conflicting reports about loratadine's effects on I HERG in different laboratories (Ducic et al, 1997;Crumb, 2000;Davie et al, 2004), we also evaluated loratadine using the Langendorff-perfused rabbit heart model. Our data show that loratadine has no significant effect on QT length at concentrations up to and including 50 M (Fig.…”

QT PRODACT: In Vivo QT Assay With a Conscious Monkey for Assessment of the Potential for Drug-Induced QT Interval Prolongation

“…Ca 2+ -channel blockers generally prolong the PR interval, and cisapride-induced PR interval prolongation has been reported in anesthetized dogs (46). Furthermore, cisapride was reported to inhibit the L-type calcium current in guinea pigs (47). The cisapride-induced tachycardia may have arisen by inhibition of the Ca 2+ -channel.…”

Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells: An In-Vitro Model to Predict Cardiac Effects of Drugs

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