Antiepileptic drugs modulate P-glycoproteins in the brain: a mice study with 11C-desmethylloperamide

Summary P-glycoprotein transporters (P-gp) located at the blood–brain barrier (BBB) are likely to play a role in refractory epilepsy. In vitro studies already pointed out that several antiepileptic drugs (AEDs) are substrate of P-gp. This study proposes a new in vivo approach to investigate the interaction between some AEDs and P-gp located at the BBB. 11 C-desmethylloperamide ( 11 C-dLop), a radiolabelled substrate of P-gp, was intravenously administrated after pretreatment with saline or AEDs (sodium valproate, levetiracetam, topiramate and phenytoin) at their human therapeutic and four times their therapeutic dose. The effect of the different pretreatment on the intracerebral concentration of 11 C-dLop was determined to indirectly investigate possible in vivo interactions between AEDs and P-gp. Pretreatment with levetiracetam, topiramate and phenytoin at therapeutic doses significantly decreased intracerebral concentration of 11 C-dLop. Pretreatment with a therapeutic dose of sodium valproate did not influence brain uptake of 11 C-dLop. In case of pretreatment with supratherapeutic doses of AED, 11 C-dLop brain uptake was not different compared to pretreatment with saline. The metabolisation rate of 11 C-dLop in plasma was unaltered, indicating that observed differences in brain uptake of the tracer were not due to pharmacokinetic changes. The following conclusion can be made: levetiracetam, topiramate and phenytoin demonstrate biphasic modulation of the BBB P-gp. At therapeutic doses they act as inducers of efflux, at supratherapeutic doses they have no effect on the efflux rate. Sodium valproate does not interact with P-gp at therapeutic nor at higher doses.