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

• Published in: British journal of pharmacology Vol. 155; no. 7; pp. 1127 - 1138
• Main Authors: Clinckers, R, Smolders, I, Michotte, Y, Ebinger, G, Danhof, M, Voskuyl, R A, Pasqua, O Della
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.12.2008; Nature Publishing Group
• Subjects: 10,11‐dihydro‐10‐hydroxy‐carbamazepine; Animals; Anticonvulsants - administration & dosage; Anticonvulsants - pharmacokinetics; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; Biological Transport; biophase kinetics; Carbamazepine - administration & dosage; Carbamazepine - analogs & derivatives; Carbamazepine - metabolism; Carbamazepine - pharmacokinetics; Chromatography, Liquid; Dose-Response Relationship, Drug; efflux transport; epilepsy; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Hippocampus - metabolism; Male; Medical sciences; Microdialysis; Models, Biological; Nervous system (semeiology, syndromes); Neurology; Neuropharmacology; Nonlinear Dynamics; NONMEM; Pharmacology. Drug treatments; population pharmacokinetic modelling; Rats; Rats, Wistar; Research Papers; Seizures - drug therapy; Seizures - physiopathology; Tissue Distribution; Population pharmacokinetics; Rat; Metabolite; Epilepsy; Biological transport; Central nervous system; 10,11 -dihydro-10-hydroxy-carbamazepine; Anticonvulsant; Encephalon; population pharmacokinetic modelling; Oxcarbazepine; Mood stabilizer; Membrane transport; Neurological disorder; biophase kinetics; efflux transport; Nervous system diseases; Rodentia; Tricyclic compound; Carbamazepine; Cerebral disorder; Vertebrata; Mammalia; Microdialysis; Convulsion; Animal; Central nervous system disease; Dibenzazepine derivatives; NONMEM
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/bjp.2008.366

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. British Journal of Pharmacology (2008) 155, 1127–1138; doi:10.1038/bjp.2008.366; published online 6 October 2008