Brain access and anticonvulsant efficacy of carbamazepine, lamotrigine, and felbamate in ABCC2/MRP2-deficient TR- rats.
OBJECTIVE
Different adenosine triphosphate (ATP)-driven multidrug transporters have been described to be expressed in the luminal membrane of blood-brain barrier (BBB) endothelial cells. At this site, multidrug transporters have been suggested to restrict penetration of drugs into the brain. Increasing evidence suggests that overexpression of different multidrug transporters occurs in the region of the epileptic focus of pharmacoresistant epilepsy patients. Based on the assumption that antiepileptic drugs (AEDs) are substrates of these transporters, this overexpression may limit access of AEDs to epileptic neurons and may contribute to drug-refractoriness. In a recent study, overexpression of multidrug resistance protein 2 (ABCC2; MRP2) was reported in BBB endothelial cells of epileptic focal tissue from pharmacoresistant patients. With brain microdialysis, we recently demonstrated that the AED phenytoin is subject to transport by ABCC2 at the BBB, whereas phenobarbital does not seem to be a substrate of ABCC2.


METHODS
We investigated whether ABCC2 is functionally involved in transport of the AEDs carbamazepine (CBZ), lamotrigine (LTG), and felbamate (FBM) across the BBB. The distribution of these AEDs into the brain of ABCC2-deficient TR- rats was determined.


RESULTS
AED concentrations in plasma and brain extracellular space of these mutant rats did not differ significantly from those of rats of the corresponding background strain. In the amygdala-kindling model of epilepsy, the anticonvulsant efficacy of LTG and FBM was comparable in both groups of rats. In contrast, CBZ exhibited a higher anticonvulsant activity in kindled ABCC2-deficient rats as compared with nonmutant rats.


CONCLUSIONS
In this present study, the microdialysis results gave no evidence that ABCC2 function modulates entry of CBZ, LTG, and FBM into the CNS of naïve rats. However, ABCC2 deficiency was associated with an increased anticonvulsant response of CBZ in the kindling model. Future investigations are planned to identify the underlying mechanism for this difference, clarifying whether a pharmacokinetic difference is detectable only when brain access of CBZ is compared in kindled ABCC2-deficient rats and kindled nonmutant rats, which may have an increased expression of ABCC2 in response to seizures. The data substantiate that ABCC2-deficient TR- rats are a useful tool for defining the role of ABCC2 for transport of AEDs, and give evidence that the use of kindled TR- rats may provide important supplementary information.
Potschka
Heidrun
H
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Bünteweg 17, D-30559 Hannover, Germany. heidrun.potschka@tiho-hannover.de
Fedrowitz
Maren
M
Löscher
Wolfgang
W
D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000502:physiology*; D002220:Carbamazepine / Q000493:pharmacokinetics* / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000235:genetics*; D004569:Electroencephalography / Q000187:drug effects; D004730:Endothelium, Vascular / Q000378:metabolism*; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism; D000078328:Felbamate; D005260:Female; D007696:Kindling, Neurologic / Q000187:drug effects / Q000235:genetics; D000077213:Lamotrigine; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000502:physiology; D048448:Phenylcarbamates; D011409:Propylene Glycols / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D014227:Triazines / Q000493:pharmacokinetics* / Q000494:pharmacology
D000927:Anticonvulsants; D002220:Carbamazepine; D000078328:Felbamate; D000077213:Lamotrigine; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D048448:Phenylcarbamates; D011409:Propylene Glycols; D014227:Triazines