Tags

Type your tag names separated by a space and hit enter

Phenytoin and phenobarbital inhibit human HERG potassium channels.
Epilepsy Res. 2003 Jun-Jul; 55(1-2):147-57.ER

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.

Authors+Show Affiliations

Division of Toxicology, Department of Pharmaceutical Biosciences, Uppsala University, Box 594, S-751 24, Uppsala, Sweden.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

12948624

Citation

Danielsson, Bengt R., et al. "Phenytoin and Phenobarbital Inhibit Human HERG Potassium Channels." Epilepsy Research, vol. 55, no. 1-2, 2003, pp. 147-57.
Danielsson BR, Lansdell K, Patmore L, et al. Phenytoin and phenobarbital inhibit human HERG potassium channels. Epilepsy Res. 2003;55(1-2):147-57.
Danielsson, B. R., Lansdell, K., Patmore, L., & Tomson, T. (2003). Phenytoin and phenobarbital inhibit human HERG potassium channels. Epilepsy Research, 55(1-2), 147-57.
Danielsson BR, et al. Phenytoin and Phenobarbital Inhibit Human HERG Potassium Channels. Epilepsy Res. 2003 Jun-Jul;55(1-2):147-57. PubMed PMID: 12948624.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phenytoin and phenobarbital inhibit human HERG potassium channels. AU - Danielsson,Bengt R, AU - Lansdell,Kate, AU - Patmore,Leslie, AU - Tomson,Torbjörn, PY - 2003/9/2/pubmed PY - 2003/10/24/medline PY - 2003/9/2/entrez SP - 147 EP - 57 JF - Epilepsy research JO - Epilepsy Res. VL - 55 IS - 1-2 N2 - 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. SN - 0920-1211 UR - https://www.unboundmedicine.com/medline/citation/12948624/Phenytoin_and_phenobarbital_inhibit_human_HERG_potassium_channels_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0920121103001190 DB - PRIME DP - Unbound Medicine ER -