The multidrug transporter hypothesis of drug resistance in epilepsy:: Proof-of-principle in a rat model of temporal lobe epilepsy

被引:182
作者
Brandt, Claudia [1 ]
Bethmann, Kerstin [1 ]
Gastens, Alexandra M. [1 ]
Loescher, Wolfgang [1 ]
机构
[1] Univ Vet Med, Dept Pharmacol Toxicol & Pharm, D-30559 Hannover, Germany
关键词
refractory epilepsy; phenobarbital; P-glycoprotein; tariquidar; blood-brain barrier;
D O I
10.1016/j.nbd.2006.06.014
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Resistance to drug treatment is an important hurdle in the therapy of many diseases, including cancer, infectious diseases and brain disorders such as epilepsy. A phenotype that is referred to as multidrug resistance was first described for chemotherapy-resistant cancer cells that over-expressed the drug efflux transporter P-glycoprotein (P-gp). More recently, overexpression of P-gp has been found in capillary endothelial cells of epileptogenic brain tissue from patients with medically intractable epilepsy. Such regionally restricted P-gp overexpression in the blood-brain barrier is likely to reduce the concentration of antiepileptic drugs at epileptic neurons, which would be a plausible explanation for multidrug resistance in epilepsy. However, a definite proof-of-principle for this hypothesis is lacking. In the present study, we used a rat model of temporal lobe epilepsy that allows selecting drug-resistant and drug-responsive subgroups of epileptic rats by prolonged treatment with the antiepileptic drug phenobarbital at maximum tolerated doses. We have shown recently that drug-resistant rats selected from this model exhibit a marked overexpression of P-gp in the hippocampus and other limbic brain regions. This model is thus ideally suited to prove the multidrug transporter hypothesis of drug resistance. For this purpose, we selected a group of phenobarbital-resistant rats, which was subsequently treated by combinations of phenobarbital with the selective P-gp inhibitor tariquidar. Coadministration of tariquidar (15-20 mg/kg) fully restored the anticonvulsant activity of phenobarbital without altering plasma pharmacokinetics or neurotoxicity of the antiepileptic drug. These data demonstrate that inhibiting P-gp in epileptic rats with proven drug resistance counteracts resistance, providing the first proof-of-principle of the multidrug transporter hypothesis of medically refractory epilepsy. (c) 2006 Elsevier Inc. All rights reserved.
引用
收藏
页码:202 / 211
页数:10
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