Quinidine Microdialysis Reveals Altered P-glycoprotein Function in Epileptic Rats in the Brain Parenchyma Rather than at the Blood-Brain Barrier
S. Syvšnen (1), M. Schenke (1), D.-J. vd Berg (1), R.A. Voskuyl (1, 2) and E.C. de Lange (1)
(1)Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands; (2)SEIN Ė Epilepsy Institutes of The Netherlands Foundation, Heemstede, The Netherlands
Objectives: Increased functionality of efflux transporters at the blood-brain barrier (BBB) may contribute to decreased drug concentrations at the target site in CNS diseases like epilepsy. In the rat, pharmacoresistant epilepsy can be mimicked by inducing status epilepticus by intraperitoneal injections of kainate. The aim of the present study was to characterise kainate induced changes in P-glycoprotein (P-gp) functionality both at the level of the blood brain barrier and brain parenchyma, using population modelling.
Methods: Quinidine, a P-gp substrate, was i.v. infused during 30 min or 4 h. Brain extra cellular fluid (free brain) concentrations were measured with microdialysis during 7 hours after start of infusion. Blood samples were obtained in parallel and brain tissue was isolated at the end of the experiment for quinidine concentration determination in plasma and brain tissue, respectively. To investigate the effect of P-gp on quinidine brain distribution, kainate and saline (control) treated rats were studied without or with pre-administration of the P-gp inhibitor tariquidar. A full pharmacokinetic model for quinidine pharmacokinetics in plasma and brain was developed using mixed effects modelling (NONMEM VI). Systematic covariate analysis was performed to identify covariates significant for changes in quinidine pharmacokinetics.
Results: Quinidine PK was best described with a 2-comp plasma and 2-comp brain model. Kainate treatment had no effect on quinidine transport across the BBB, but produced a 1.7-fold decrease of the volume of distribution in the brain. Tariquidar pre-treatment was found to be a significant covariate, for quinidine transport across the BBB, producing a 2.7-fold increase in transport into the brain and a 2.6-fold decrease in transport out from the brain. Tariquidar also increased the distribution from the free brain compartment to the deeper brain compartment 5.6-fold. The effect of tariquidar was similar in kainate and control rats.
Conclusions: This study did not confirm the hypothesis that P-gp functionality at the BBB is altered in epilepsy, but rather indicated that the P-gp function might be changed at the parenchymal level. Quinidine distribution into the free brain compartment was increased more than 7-fold after tariquidar treatment. Interestingly, tariquidar also increased the distribution from the free to the deeper brain compartment, again, indicating that the P-gp function beyond the BBB should be further investigated.