Inhibition of the multidrug transporter P-glycoprotein improves seizure control in phenytoin-treated chronic epileptic rats
van Vliet EA, van Schaik R, Edelbroek PM, Redeker S, Aronica E, Wadman WJ, et al.;
Commented by , 23 May 2006
Background
Animal and human studies have shown that drug transporter systems, including P-glycoprotein, are upregulated in epileptic brain tissue (ref. 1).
The hypothesis has been made that increased transporter-mediated efflux limits access of antiepileptic drugs (AEDs) to the site of action, resulting in pharmacoresistance (ref. 2; ref. 3; ref. 4; ref. 5; ref. 6).
Aim
To determine whether inhibition of P-glycoprotein reverses pharmacoresistance in a rat model of temporal lobe epilepsy.
Methods
- Status epilepticus was induced in rats by repeated electrical stimulation of the hippocampus
- After a period of 4-5 months, animals presented with spontaneous daily seizures
- Rats were then treated with phenytoin alone or in combination with the P-glycoprotein inhibitor tariquidar. Each treatment lasted 7-days, with 2-week wash-outs between treatments.
Results
- Phenytoin alone was only partially effective in suppressing seizures. Tariquidar given without phenytoin was without effect
- Almost complete seizure control was obtained when phenytoin and tariquidar were given together; however, the greater efficacy of the combination only lasted for 3 or 4 days, and was no longer present thereafter
- Compared with control (non-epileptic) rats, epileptic rats showed markedly up-regulated levels of P-glycoprotein in the brain, together with a 20% reduction in brain phenytoin levels. Brain phenytoin levels were increased after two doses of tariquidar.
Professor Perucca's comments
P-glycoprotein (MDR1) and multidrug resistance-associated proteins 1 (MRP1) and 2 (MRP2) have been reported to modulate the transport of phenytoin, phenobarbital, topiramate, valproate, lamotrigine, felbamate and, possibly, carbamazepine, across the blood brain barrier (ref. 7; ref. 8; ref. 9; ref. 10).
Up-regulation of these transporters has been observed in epileptogenic tissue in animals and humans, possibly limiting the access of AEDs to the epileptic focus (ref. 1; ref. 2; ref. 3; ref. 4; ref. 5; ref. 6; ref. 11; ref. 12; ref. 13; ref. 14).
In previous studies, inhibition of multidrug transporters was found to potentiate the activity of AEDs against evoked seizures in some models (ref. 10; ref. 15), but the effect of specific P-glycoprotein inhibitors was not investigated. Van Vliet’s and colleagues now provide proof of principle that specific inhibition of P-glycoprotein enhances the efficacy of phenytoin in animals with spontaneous seizures. These results agree with those presented recently in abstract form by German scientists (ref. 16), who found tariquidar effective in reversing phenobarbital resistance in a similar rat model (ref. 17) of temporal lobe epilepsy.
A potential beneficial effect of drug transporters modulators on human refractory seizures has been suggested by very preliminary reports of improved seizure control in two AED-treated patients after administration of the non-specific P-glycoprotein inhibitor verapamil (ref. 18; ref. 19). Verapamil, however, is also a cytochrome P450 inhibitor, which interacts adversely with many AEDs (ref. 20).
P-glycoprotein inhibition might represent a useful streategy against refractory epilepsy, but excitement with available findings should be tempered by various considerations:
- Van Vliet and coworkers only tested one dosage of phenytoin, and it is unclear whether higher doses would have controlled seizures without tariquidar. In any case, it remains to be established whether tariquidar increases AED access in epileptogenic tissue only, or whether increased AED exposure extends to other brain areas. If tariquidar effects were widespread, the benefits of added anticonvulsant activity could be negated by enhanced toxicity
- Toxicity concerns with P-glycoprotein inhibitors are reinforced by evidence that higher inhibitor concentrations may be needed to block P-glycoprotein in the brain than in other tissues (ref. 21). The consequences of prolonged P-glycoprotein inhibition on brain function also remain to be determined
- Tolerance developed to the effects of tariquidar in Val Vliet’s study. Although this phenomenon was surprisingly under-emphasized, it is a very serious concern and requires further investigation to clarify underlying mechanisms
- Drug resistance in epilepsy is probably multifactorial (ref. 1; ref. 2; ref. 3; ref. 4; ref. 5; ref. 6). Changes may occur in other transporter systems (ref. 3; ref. 5), drug sequestration mechanisms (ref. 22) and AED target sites (ref. 6), suggesting that inhibition of P-glycoprotein alone could be of limited value. Indeed, in the clinic, AED refractoriness extends to AEDs which are not substrates of P-glycoprotein (ref. 6)
- Results of cancer studies indicate that promising results in animal models may not be always paralleled by comparable benefits in the clinical setting (ref. 23).
In conclusion, the drug transporter hypothesis of pharmacoresistance remains an attractive area for research. Far more laboratory work, however, is needed before this hypothesis can be taken meaningfully to proper testing in patients with refractory epilepsy.
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