QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.049858v1 jpet.103.049858v2 306/1/124    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Potschka, H. Articles by Löscher, W. Search for Related Content PubMed PubMed Citation Articles by Potschka, H. Articles by Löscher, W.

NEUROPHARMACOLOGY

Multidrug Resistance Protein MRP2 Contributes to Blood-Brain Barrier Function and Restricts Antiepileptic Drug Activity

Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, Germany

The blood-brain barrier (BBB) is a physical and metabolic barrier between the brain and the systemic circulation, which functions to protect the brain from circulating drugs, toxins, and xenobiotics. ATP-dependent multidrug transporters such as P-glycoprotein (Pgp; ABCB1), which are found in the apical (luminal) membranes of brain capillary endothelial cells, are thought to play an important role in BBB function by limiting drug penetration into the brain. More recently, the multidrug resistance protein MRP2 (ABCC2) has been found in the luminal surface of brain capillary endothelium of different species, including humans. In endothelial cells from patients with drug-resistant epilepsy, MRP2 was shown to be overexpressed, indicating that it may be critically involved in multidrug resistance of such patients. However, the role of MRP2 in drug disposition into the brain is defined poorly. Herein, we used different strategies to study the contribution of MRP2 to BBB function. First, the MRP inhibitor probenecid was shown to increase extracellular brain levels of the major antiepileptic drug phenytoin in rats, indicating that phenytoin is a substrate of MRP2 in the BBB. This was substantiated by using MRP2-deficient TR– rats, in which extracellular brain levels of phenytoin were significantly higher compared with the normal background strain. In the kindling model of epilepsy, coadministration of probenecid significantly increased the anticonvulsant activity of phenytoin. In kindled MRP2-deficient rats, phenytoin exerted a markedly higher anticonvulsant activity than in normal rats. These data indicate that MRP2 substantially contributes to BBB function.

Address correspondence to: Dr. W. Löscher, Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Bünteweg 17, D-30559 Hannover, Germany. E-mail: wolfgang.loescher{at}tiho-hannover.de

This article has been cited by other articles:

				R. Zhao, T. J. Raub, G. A. Sawada, S. C. Kasper, J. A. Bacon, A. S. Bridges, and G. M. Pollack Breast Cancer Resistance Protein Interacts with Various Compounds in Vitro, but Plays a Minor Role in Substrate Efflux at the Blood-Brain Barrier Drug Metab. Dispos., June 1, 2009; 37(6): 1251 - 1258. [Abstract] [Full Text] [PDF]

				X. Liu, C. Chen, and B. J. Smith Progress in Brain Penetration Evaluation in Drug Discovery and Development J. Pharmacol. Exp. Ther., May 1, 2008; 325(2): 349 - 356. [Abstract] [Full Text] [PDF]

				E. A. van Vliet, R. van Schaik, P. M. Edelbroek, R. A. Voskuyl, S. Redeker, E. Aronica, W. J. Wadman, and J. A. Gorter Region-Specific Overexpression of P-glycoprotein at the Blood-Brain Barrier Affects Brain Uptake of Phenytoin in Epileptic Rats J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 141 - 147. [Abstract] [Full Text] [PDF]

				S. Baltes, M. Fedrowitz, C. L. Tortos, H. Potschka, and W. Loscher Valproic Acid Is Not a Substrate for P-glycoprotein or Multidrug Resistance Proteins 1 and 2 in a Number of in Vitro and in Vivo Transport Assays J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 331 - 343. [Abstract] [Full Text] [PDF]

				S. Dallas, D. S. Miller, and R. Bendayan Multidrug resistance-associated proteins: expression and function in the central nervous system. Pharmacol. Rev., June 1, 2006; 58(2): 140 - 161. [Abstract] [Full Text] [PDF]

				B. M. Johnson, P. Zhang, J. D. Schuetz, and K. L. R. Brouwer CHARACTERIZATION OF TRANSPORT PROTEIN EXPRESSION IN MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN (MRP) 2-DEFICIENT RATS Drug Metab. Dispos., April 1, 2006; 34(4): 556 - 562. [Abstract] [Full Text] [PDF]

				S. Remy and H. Beck Molecular and cellular mechanisms of pharmacoresistance in epilepsy Brain, January 1, 2006; 129(1): 18 - 35. [Abstract] [Full Text] [PDF]

				L. M. Augustine, R. J. Markelewicz Jr., K. Boekelheide, and N. J. Cherrington XENOBIOTIC AND ENDOBIOTIC TRANSPORTER MRNA EXPRESSION IN THE BLOOD-TESTIS BARRIER Drug Metab. Dispos., January 1, 2005; 33(1): 182 - 189. [Abstract] [Full Text] [PDF]

				T. S. Maurer, D. B. DeBartolo, D. A. Tess, and D. O. Scott RELATIONSHIP BETWEEN EXPOSURE AND NONSPECIFIC BINDING OF THIRTY-THREE CENTRAL NERVOUS SYSTEM DRUGS IN MICE Drug Metab. Dispos., January 1, 2005; 33(1): 175 - 181. [Abstract] [Full Text] [PDF]

				B. Bauer, A. M. S. Hartz, G. Fricker, and D. S. Miller Pregnane X Receptor Up-Regulation of P-Glycoprotein Expression and Transport Function at the Blood-Brain Barrier Mol. Pharmacol., September 1, 2004; 66(3): 413 - 419. [Abstract] [Full Text] [PDF]