Background & Objective: 

Accurate prediction of biophase pharmacokinetics is essential to optimise pharmacotherapy in epilepsy. The present study was conducted to characterise the pharmacokinetics of 10-hydroxycarbazepine (MHD) in plasma and in the hippocampus. Simultaneously, the impact of acute seizures and P-glycoprotein mechanisms on brain distribution was quantified.

Methods and results: 

Rats received sub-therapeutic and anticonvulsant doses of MHD in non-epileptic conditions and during focal pilocarpine-induced limbic seizures. To evaluate the effect of P-glycoprotein transport blockade, a separate group received sub-therapeutic doses combined with intrahippocampal perfusion of verapamil. Free plasma and extracellular hippocampal MHD concentrations were determined using microdialysis and LC techniques. An integrated pharmacokinetic model describing simultaneously the pharmacokinetics 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. A compartmental model with combined zero and first-order absorption, including lag time and biophase distribution best described the pharmacokinetics of MHD. A distributional process seems to underlie the increase in brain MHD concentrations observed following seizure activity and P-glycoprotein blockade, as reflected by changes in the volume of distribution of the biophase compartment. In contrast, no changes were observed in plasma pharmacokinetics.

Conclusions: 

Simultaneous pharmacokinetic modelling of plasma and brain concentrations has not been used previously in the evaluation of antiepileptic drugs. Characterisation of biophase pharmacokinetics is critical to assess the impact of P-glycoprotein-mediated transport and acute seizures on brain disposition and consequently on the effects of antiepileptic drugs.