Abstracts

Rationale: There are two main hypotheses for drug-resistance in epilepsy: the target- and the transporter-hypothesis. As part of a positron emission tomography study investigating multidrug transporter function, we injected the selective, third-generation P-glycoprotein (P-gp) inhibitor Tariquidar (TQD) into three patients with drug-resistant temporal lobe epilepsy (TLE) and six healthy controls. Here, we report the clinical response to this intervention. Methods: TQD was injected intra-venously at a dose of 2mg/kg over 30 minutes at a standardised time of about 1pm. All patients had tried at least 5 anti-epileptic drugs (AEDs) at maximum-tolerated doses without achieving seizure-control and were currently treated with a combination of Phenytoin (325mg) and clobazam (40mg) (No 1), Lamotrigine (200mg) and Pregabalin (300mg) (No 2), and Carbamazepine (1000mg), Levetiracetam (3000mg), Valproate (2500mg) and Zonisamide (150mg) (No 3). Results: All subjects tolerated TQD-infusion well without any complication with the exception of one healthy control who complained about light-headedness with her blood pressure dropping to 75/40 mmHg, but she recovered quickly following elevation of her legs. One of the three patients (patient No 3) reported side-effects, such as blurred vision, nausea and ataxia, starting about 24 hours after the end of the TQD-infusion. Side-effects increased in severity over the next 24 hours, during which she continued to take her regular AEDs. The side-effects subsided once Carbamazepine, Valproate and Zonisamide were omitted about 60 hours after TQD infusion. Carbamazepine levels at this time of maximum intoxication were measured at 6mg/l. Following TQD infusion, the patient has not experienced any seizures for the last 4 weeks, whilst experiencing complex-partial seizures previously at a rate of 2-3 month. Conclusions: Our preliminary findings support the notion of drug-transporter-mediated pharmacoresistance. CBZ levels were not raised at a time, when the patient reported CBZ-specific side-effects. The timeline of the reported side-effects are in keeping with the elimination half-life of tariquidar (18-36 hours) resulting in accumulation of AEDs in the brain parenchyma, but not in blood, due to reduced efflux-transport of AEDs from the brain to blood compartments.