Phenytoin and phenobarbital inhibit human HERG potassium channels
Danielsson BR, Lansdell K, Patmore L, and Tomson T(2003) Phenytoin and phenobarbital inhibit human herg potassium channels. Epilepsy Res 55:1-2 147–57.
Abstract: Drugs that inhibit the cardiac rapid delayed rectifier potassium ion current (IKr) channel can be proarrhythmic and their clinical use has been associated with sudden unexpected death (SUD). Since SUD is about 20 times more common among people with epilepsy than in the general population, and some data indicate that drug treatment may contribute, we tested the hypothesis that the classic antiepileptic drugs phenytoin (PHT), carbamazepine (CBZ), and phenobarbital (PB) have a potential to block IKr. The whole cell patch-clamp recording technique was used to study the effects on IKr channels expressed by the human ether-a-go-go related gene (HERG) stably expressed in Human Embryo Kidney (HEK) 293 cells. Tail currents, which are purely related to HERG, were blocked with an IC50 (the concentration when 50% inhibition was obtained compared to control values) of 240 microM for PHT and 3 mM for PB. A 20% inhibition of tail currents was obtained at CBZ concentrations of 250 and 500 microM. Collective data show that drugs with the same margins (ratio HERG IC50/unbound therapeutic concentration), as PHT and PB, may have arrhythmogenic potential, especially when used in predisposed patients and in the case of drug-drug interactions. SUD in epilepsy is generally a seizure-related phenomenon. However, our data suggest that PHT and PB may play a contributing role, perhaps by making some patients more vulnerable to the cardiovascular depression induced by seizures.
Keywords: Phenytoin; Phenobarbital; Carbamazepine; HERG; IKr; Sudden death
Context
Test of effects of PHT, CBZ, and PB on inward-rectifying potassium conductance IKr in HEK cells. PHT and PB blocked the channel at doses comparable to those expected to be unbound in some patients, especially if taking other drugs that reduced clearance or binding.