Impact of efflux transporters and of seizures on the pharmacokinetics of oxcarbazepine metabolite in the rat brain

Abstract

Background and purpose: 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.

Experimental approach: 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.

Key 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 and implications: 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.

Figure 1

Experimental set-up. Timescale showing plasma and dialysate collection time intervals (in minutes) and continuous perfusion periods for the different intrahippocampally applied compounds. Microdialysis probe position is schematically depicted in the hippocampal CA1–CA3 region.

Figure 2

Semilogarithmic plots of unbound plasma and brain extracellular (EC) fluid 10,11-dihydro-10-hydroxy-carbamazepine (MHD) concentration–time profiles following i.p. administration in a typical control rat, rat with pilocarpine-induced seizures and rat with concomitant efflux transport inhibition through intracerebral verapamil perfusion.

Figure 3

A schematic overview of the population pharmacokinetic model for 10,11-dihydro-10-hydroxy-carbamazepine (MHD) describing the pharmacokinetics in plasma and brain simultaneously. The model consists of a central compartment with combined zero- and first-order absorption with lag time and biophase distribution (V, volume of distribution; k_a, absorption rate constant; k, elimination rate constant; k₂₃, k₃₂, transfer rate constants between central and effect compartment).

Figure 4

Goodness-of-fit plots obtained for the final population pharmacokinetic model. Scatter plots show the observed 10,11-dihydro-10-hydroxy-carbamazepine (MHD) plasma (a) and brain (b) concentrations versus the individual (IPRED) and population (PRED) predictions; conditional weighed residuals (CWRES) are depicted against individual predicted plasma (c) and brain (d) concentration and against time for plasma (e) and brain (f).

Figure 5

Pharmacokinetics of 10,11-dihydro-10-hydroxy-carbamazepine (MHD) in plasma and brain in control conditions, during acute seizures and during efflux transport inhibition following i.p. administration of a subtherapeutic MHD dose (20 mg kg⁻¹). Observed values and population predictions with 2.5 and 97.5% quantiles are shown.

Figure 6

Pharmacokinetics of 10,11-dihydro-10-hydroxy-carbamazepine (MHD) in plasma and brain in control conditions and during acute seizures following intraperitoneal administration of subtherapeutic MHD doses (40 and 60 mg kg⁻¹). Observed values and population predictions with 2.5 and 97.5% quantiles are shown for each dosing group.

Figure 7

Pharmacokinetics of 10,11-dihydro-10-hydroxy-carbamazepine (MHD) in plasma and brain in control conditions and during acute seizures following intraperitoneal administration of anticonvulsant MHD doses (80, 100 and 150 mg kg⁻¹). Observed values and population predictions with 2.5 and 97.5% quantiles are shown for each dosing group.