Effects of cocaine and its major metabolites on the HERG-encoded potassiumchannel

Cocaine abuse has been reported to result in QT prolongation in humans; how ever, the mechanisms underlying this effect are still poorly understood. In this study we compared the direct effects of cocaine and its major metabol ites in human embryonic kidney 293 cells stably transfected with human othe r-ago-go-related gene (HERG). Cocaine blocked HERG-encoded potassium channe ls with an IC50 of 4.4 +/-1.1 muM (22 degreesC). Cocaethylene (a metabolite formed in the presence of ethanol) had a significantly lower IC50 of 1.2 d egrees +/-1.1 muM (P<0.0001), and cocaine's primary pyrolysis metabolite me thylecgonidine blocked HERG with a higher IC50 of 171.7<plus/minus>1.2 muM. In contrast, 1 mM ecgonine methylester or benzoylecgonine produced only a minimal block (21 +/-4 and 15 +/-8%, respectively). Blockade of HERG by coc aine, cocaethylene, and methylecgonidine increased significantly over the v oltage range where HERG activates, but became constant at voltages where HE RG activation was maximal, indicating that all three drugs block open chann els, but by a mechanism that is not highly sensitive to voltage per se. Coc aine and cocaethylene also significantly slowed the time course of deactiva tion at -60 mV, an effect consistent with open channel block. We conclude t hat 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 c oncentrations.