Abstract

Cocaine abuse has been reported to result in QT prolongation in humans; however, the mechanisms underlying this effect are still poorly understood. In this study we compared the direct effects of cocaine and its major metabolites in human embryonic kidney 293 cells stably transfected with human ether-a-go-go-related gene (HERG). Cocaine blocked HERG-encoded potassium channels with an IC₅₀ of 4.4 ± 1.1 μM (22°C). Cocaethylene (a metabolite formed in the presence of ethanol) had a significantly lower IC₅₀ of 1.2 ± 1.1 μM (P < 0.0001), and cocaine's primary pyrolysis metabolite methylecgonidine blocked HERG with a higher IC₅₀ of 171.7 ± 1.2 μM. In contrast, 1 mM ecgonine methylester or benzoylecgonine produced only a minimal block (21 ± 4 and 15 ± 8%, respectively). Blockade of HERG by cocaine, cocaethylene, and methylecgonidine increased significantly over the voltage range where HERG activates, but became constant at voltages where HERG activation was maximal, indicating that all three drugs block open channels, but by a mechanism that is not highly sensitive to voltage per se. Cocaine and cocaethylene also significantly slowed the time course of deactivation at −60 mV, an effect consistent with open channel block. We conclude that cocaethylene is slightly more potent than cocaine as a blocker of HERG, whereas methylecgonidine has much lower potency, and both benzoylecgonine and ecgonine methyl ester are essentially inactive at clinically relevant concentrations.