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van Vliet EA, van Schaik R, Edelbroek PM, Redeker S, Aronica E, Wadman WJ, Marchi N, Vezzani A, Gorter JA.
Epilepsia 2006;47: 672–680. [PubMed]
Overexpression of multidrug transporters such as P-glycoprotein (P-gp) may play a significant role in pharmacoresistance, by preventing antiepileptic drugs (AEDs) from reaching their targets in the brain. Until now, many studies have described increased P-gp expression in epileptic tissue or have shown that several AEDs act as substrates for P-gp. However, definitive proof showing the functional involvement of P-gp in pharmacoresistance is still lacking. Here we tested whether P-gp contributes to pharmacoresistance to phenytoin (PHT) by using a specific P-gp inhibitor in a model of spontaneous seizures in rats.
The effects of PHT on spontaneous seizure activity were investigated in the electrical post-status epilepticus rat model for temporal lobe epilepsy, before and after administration of tariquidar (TQD), a selective inhibitor of P-gp.
A 7-day treatment with therapeutic doses of PHT suppressed spontaneous seizure activity in rats, but only partially. However, an almost complete control of seizures by PHT (93%± 7%) was obtained in all rats when PHT was coadministered with TQD. This specific P-gp inhibitor was effective in improving the anticonvulsive action of PHT during the first 3–4 days of the treatment. Western blot analysis confirmed P-gp upregulation in epileptic brains (140–200% of control levels), along with approximately 20% reduced PHT brain levels. Inhibition of P-gp by TQD significantly increased PHT brain levels in chronic epileptic rats.
These findings show that TQD significantly improves the anticonvulsive action of PHT, thus establishing a proof-of-concept that the administration of AEDs in combination with P-gp inhibitors may be a promising therapeutic strategy in pharmacoresistant patients.
The three pillars of guilt will be instantly recognizable to viewers of television cop shows and courtroom dramas. Means, motive, and opportunity often need to be established to secure a successful prosecution in criminal proceedings. A very similar set of criteria can be considered essential in assessing the validity of biological mechanisms that contribute to disease or shape the individual characteristics of that disease. Just like the detective, it is incumbent on the scientist to establish burden of proof and to provide evidence that is beyond any reasonable doubt.
The issue of pharmacoresistance in epilepsy has received considerable attention in recent years, and the search for mechanisms that might explain why 35% of patients fail to respond to current medications continues apace. A number of plausible hypotheses have been proposed, including inadequate penetration of antiepileptic drugs (AEDs) across the blood–brain barrier; acquired alterations to the structure and/or functionality of ion channels and neurotransmitter receptors that represent the principal targets of AEDs; the narrow pharmacological spectrum, and thereby, inadequacy of current agents; and an inherent resistance, governed by genetic variants of proteins involved in the pharmacokinetics and pharmacodynamics of AED action (1). Of these, the so-called transporter hypothesis, which describes the active extrusion of antiepileptic agents from their intended site of action, is the most extensively researched and documented.
Drug-transporter proteins are expressed throughout the body and control the transfer of endogenous and exogenous molecules across biological membranes. They are predominantly expressed in organs with excretory functions, such the gastrointestinal tract, liver, and kidney, but also protect sensitive tissues, including the brain, placenta, and testes, from potentially toxic xenobiotics (2). The transporter hypothesis of drug-resistant epilepsy is founded on the premise that overexpression of drug transporting proteins at the blood–brain barrier prevents AEDs from reaching the interstitial space and, thereby, exerting their pharmacodynamic effects. There are, of course, several caveats to this proposition, and these have been elegantly summarized in four specific criteria (3), which represent the “means, motive and opportunity” of the drug-transporter hypothesis.
The manuscript by van Vliet and colleagues provides support, at least on some level, for all four of the criteria discussed earlier: overexpression of P-gp in a model of epilepsy, evidence to suggest that phenytoin is a substrate for P-gp–mediated extrusion, a demonstration of transporter up-regulation in the causation of drug-resistant seizures, and the reversal of pharmacoresistance by selective inhibition. Of minor concern in this study is the apparently transient effect of P-gp inhibition, the unconvincing efforts to exclude an anticonvulsant effect of tariquidar, the failure to quantify any change in the tolerability profile of phenytoin, and the unusual decision to analyze drug concentrations in the epileptic region alone. Despite these limitations, the experimental evidence offered by van Vliet et al. is relatively compelling. It is perfectly reasonable to conclude that P-gp plays a significant role in mediating resistance to AEDs in animal models of epilepsy and that inhibition of P-gp can circumvent this mechanism, but whether this phenomenon extends to other drug-transporter proteins or to the clinical arena remains unclear.
Principles of clinical pharmacology dictate that pharmacokinetic barriers to drug action, such as enhanced hepatic metabolism or augmented efflux from the brain, should be surmountable by successive increases in dose. This principle does not apply clinically in the case of intractable epilepsy and, thus far, has not been specifically evaluated in experimental models of refractory seizures. From a clinical standpoint, there is little direct or indirect evidence to support the assertion that AEDs are sufficiently strong substrates for transporter-mediated extrusion from the brain to account for their wholesale lack of efficacy. This premise is supported by data from laboratory studies that suggest compounds, such as phenytoin, are much more effectively transported by rodent P-gp than the human equivalent (12). It is entirely possible that all of this fascinating and at times, convenient evidence applies only to rodents. There is little doubt that the drug-transporter hypothesis of refractory epilepsy has biological plausibility—that is, means, motive, and opportunity have been proven in the laboratory. This assertion is great news for rats with refractory epilepsy but the evidence to suggest that culpability extends to the human species remains largely circumstantial and, as yet, is unlikely to stand up in a court of law.