Cerebral uptake of drugs and pharmacoresistance in epilepsy.

Ralph Clinckers, Ilse Julia Smolders, Yvette Michotte, Guy Ebinger, M. Danhof, Ra Voskuyl, O Della Pasqua

Research output: Chapter in Book/Report/Conference proceedingMeeting abstract (Book)Research

Abstract

The blood-brain barrier (BBB) governs drug access to the brain and hence is a crucial determinant in biophase availability of CNS drugs. Several classes of efflux transporters are present at the level of the BBB and at the cellular membranes of parenchyma cells and are considered to act in tandem in hindering efficient drug delivery to the brain. Over-expression of active efflux mechanisms has been described in epileptic brain areas and is suggested to play a substantial role in pharmacoresistance to antiepileptic drugs. In that context we demonstrated that therapeutic failure of oxcarbazepine (OXC) against chemoconvulsant-evoked seizures can be reversed by co-administration of multidrug efflux transporter inhibitors. The epilepsies are known to compromise the integrity and selective permeability of the BBB causing regional concentration differences within the brain. Indeed, the brain may not be considered a priori a homogeneous compartment and multiple factors govern drug distribution into and within the brain compartments, some of which can be affected during pathological conditions. Accurate prediction of biophase pharmacokinetics is therefore essential to optimise pharmacotherapy in epilepsy. We developed an integrated PK model characterising simultaneously the pharmacokinetics of 10-hydroxycarbazepine (MHD), the active metabolite of OXC, in rat plasma and in hippocampal microdialysates using nonlinear mixed effects modelling. Concomitantly, the impact of acute seizures and efflux transport mechanisms on brain distribution was quantified. Biophase disposition of AEDs was shown to differ significantly from plasma pharmacokinetics. BBB transport and brain distribution was demonstrated to be importantly restricted by efflux transporters. Moreover, we showed that the plasma-brain interrelationship is altered by seizure activity and that drug redistribution within the brain is likely to be involved. These results support that characterisation of target tissue distribution in control and pathological conditions is imperative for accurate dosing rationale.
Original languageEnglish
Title of host publicationDutch Endo-Neuro-Psycho-meeting 2008, Doorwerth, The Netherlands
Publication statusPublished - 2008
EventFinds and Results from the Swedish Cyprus Expedition: A Gender Perspective at the Medelhavsmuseet - Stockholm, Sweden
Duration: 21 Sep 200925 Sep 2009

Publication series

NameDutch Endo-Neuro-Psycho-meeting 2008, Doorwerth, The Netherlands

Conference

ConferenceFinds and Results from the Swedish Cyprus Expedition: A Gender Perspective at the Medelhavsmuseet
Country/TerritorySweden
CityStockholm
Period21/09/0925/09/09

Keywords

  • pharmacokinetic modelling
  • epilepsy
  • oxcarbazepine

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