Impact of efflux transporters and of seizures on the pharmacokinetics of oxcarbazepine metabolite in the rat brain.
OBJECTIVE
Accurate prediction of biophase pharmacokinetics (PK) is essential to optimize pharmacotherapy in epilepsy. Here, we characterized the PK of the active metabolite of oxcarbazepine, 10,11-dihydro-10-hydroxy-carbamazepine (MHD) in plasma and in the hippocampus. Simultaneously, the impact of acute seizures and efflux transport mechanisms on brain distribution was quantified.


METHODS
Rats received subtherapeutic and anticonvulsant doses of MHD in non-epileptic conditions and during focal pilocarpine-induced limbic seizures. To evaluate the effect of efflux transport blockade, a separate group received subtherapeutic doses combined with intrahippocampal perfusion of verapamil. Free plasma and extracellular hippocampal MHD concentrations were determined using microdialysis and liquid chromatography techniques. An integrated PK model describing simultaneously the PK of MHD in plasma and brain was developed using nonlinear mixed effects modelling. A bootstrap procedure and a visual predictive check were performed to assess model performance.


RESULTS
A compartmental model with combined zero- and first-order absorption, including lag time and biophase distribution best described the PK of MHD. A distributional process appeared to underlie the increased brain MHD concentrations observed following seizure activity and efflux transport inhibition, as reflected by changes in the volume of distribution of the biophase compartment. In contrast, no changes were observed in plasma PK.


CONCLUSIONS
Simultaneous PK modelling of plasma and brain concentrations has not been used previously in the evaluation of antiepileptic drugs (AEDs). Characterisation of biophase PK is critical to assess the impact of efflux transport mechanisms and acute seizures on brain disposition and, consequently, on AED effects.
Clinckers
R
R
Department of Pharmaceutical Chemistry and Drug Analysis (labo FASC), Farmaceutisch Instituut-Gebouw G, Vrije Universiteit Brussel, Brussels, Belgium.
Smolders
I
I
Michotte
Y
Y
Ebinger
G
G
Danhof
M
M
Voskuyl
R A
RA
Della Pasqua
O
O
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001692:Biological Transport; D002220:Carbamazepine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D008954:Models, Biological; D017711:Nonlinear Dynamics; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000188:drug therapy* / Q000503:physiopathology; D014018:Tissue Distribution
C039775:10,11-dihydro-10-hydroxycarbamazepine; D000927:Anticonvulsants; C476610:oxcarbamazepine; D002220:Carbamazepine