, Volume 2, Issue 1, pp 86–98 | Cite as

Blood-brain barrier active efflux transporters: ATP-binding cassette gene family

  • Wolfgang Löscher
  • Heidrun Potschka


The blood-brain barrier (BBB) contributes to brain homeostasis by protecting the brain from potentially harmful endogenous and exogenous substances. BBB active drug efflux transporters of the ATP-binding cassette (ABC) gene family are increasingly recognized as important determinants of drug distribution to, and elimination from, the CNS. The ABC efflux transporter P-glycoprotein (Pgp) has been demonstrated as a key element of the BBB that can actively transport a huge variety of lipophilic drugs out of the brain capillary endothelial cells that form the BBB. In addition to Pgp, other ABC efflux transporters such as members of the multidrug resistance protein (MRP) family and breast cancer resistance protein (BCRP) seem to contribute to BBB function. Consequences of ABC efflux transporters in the BBB include minimizing or avoiding neurotoxic adverse effects of drugs that otherwise would penetrate into the brain. However, ABC efflux transporters may also limit the central distribution of drugs that are beneficial to treat CNS diseases. Furthermore, neurological disorders such as epilepsy may be associated with overexpression of ABC efflux transporters at the BBB, resulting in pharmacoresistance to therapeutic medication. Therefore, modulation of ABC efflux transporters at the BBB forms a novel strategy to enhance the penetration of drugs into the brain and may yield new therapeutic options for drug-resistant CNS diseases.

Key Words

P-glycoprotein multidrug resistance proteins epilepsy antiepileptic drugs depression AIDS 


  1. 1.
    Jones PM, George AM. The ABC transporter structure and mechanism: perspectives on recent research.Cell Mol Life Sci 61: 682–699, 2004.PubMedCrossRefGoogle Scholar
  2. 2.
    Borges-Walmsley MI, McKeegan KS, Walmsley AR. Structure and function of efflux pumps that confer resistance to drugs.Biochem J 376: 313–338, 2003.PubMedCrossRefGoogle Scholar
  3. 3.
    Silverman JA. Multidrug-resistance transporters.Pharm Biotechnol 12: 353–386, 1999.PubMedCrossRefGoogle Scholar
  4. 4.
    Fromm MF. P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs.Int J Clin Pharmacol Ther 38: 69–74, 2000.PubMedGoogle Scholar
  5. 5.
    Litman T, Druley TE, Stein WD, Bates SE. From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance.Cell Mol Life Sci 58: 931–959, 2001.PubMedCrossRefGoogle Scholar
  6. 6.
    Schinkel AH, Jonker JW. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview.Adv Drug Deliv Rev 55: 3–29, 2003.PubMedCrossRefGoogle Scholar
  7. 7.
    Lin JH. How significant is the role of P-glycoprotein in drug absorption and brain uptake?Drugs Today (Barc) 40: 5–22, 2004.CrossRefGoogle Scholar
  8. 8.
    Fromm MF. Importance of P-glycoprotein for drug disposition in humans.Eur J Clin Invest 33[Suppl 2]: 6–9, 2003.PubMedCrossRefGoogle Scholar
  9. 9.
    Sun H, Dai H, Shaik N, Elmquist WF. Drug efflux transporters in the CNS.Adv Drug Deliv Rev 55: 83–105, 2003.PubMedCrossRefGoogle Scholar
  10. 10.
    Schinkel AH. P-Glycoprotein, a gatekeeper in the blood-brain barrier.Adv Drug Deliv Rev 36: 179–194, 1999.PubMedCrossRefGoogle Scholar
  11. 11.
    Pardridge WM. Blood-brain barrier biology and methodology.J Neurovirol 5: 556–569, 1999.PubMedCrossRefGoogle Scholar
  12. 12.
    Graff CL, Pollack GM. Drug transport at the blood-brain barrier and the choroid plexus.Curr Drug Metab 5: 95–108, 2004.PubMedCrossRefGoogle Scholar
  13. 13.
    Gerk PM, Vore M. Regulation of expression of the multidrug resistance-associated protein 2 (MRP2) and its role in drug disposition.J Pharmacol Exp Ther 302: 407–415, 2002.PubMedCrossRefGoogle Scholar
  14. 14.
    Flicker G, Miller DS. Modulation of drug transporters at the blood-brain barrier.Pharmacology 70: 169–176, 2004.CrossRefGoogle Scholar
  15. 15.
    Begley DJ. ABC transporters and the blood-brain barrier.Curr Pharm Des 10: 1295–1312, 2004.PubMedCrossRefGoogle Scholar
  16. 16.
    Lee G, Dallas S, Hong M, Bendayan R. Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations.Pharmacol Rev 53: 569–596, 2001.PubMedGoogle Scholar
  17. 17.
    Golden PL, Pollack GM. Blood-brain barrier efflux transport.J Pharm Sci 92: 1739–1753, 2003.PubMedCrossRefGoogle Scholar
  18. 18.
    Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants.Biochim Biophys Acta 455: 152–162, 1976.PubMedCrossRefGoogle Scholar
  19. 19.
    Cordon-Cardo C, O’Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, Bertino JR. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites.Proc Natl Acad Sci USA 86: 695–698, 1989.PubMedCrossRefGoogle Scholar
  20. 20.
    Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC. Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P170: evidence for localization in brain capillaries and crossreactivity of one antibody with a muscle protein.J Histochem Cytochem 37: 159–164, 1989.PubMedCrossRefGoogle Scholar
  21. 21.
    Demeule M, Regina A, Jodoin J, Laplante A, Dagenais C, Berthelet F, Moghrabi A, Beliveau R. Drug transport to the brain: key roles for the efflux pump P-glycoprotein in the blood-brain barrier.Vascul Pharmacol 38: 339–348, 2002.PubMedCrossRefGoogle Scholar
  22. 22.
    Sawchuk RJ, Elmquist WF. Microdialysis in the study of drug transporters in the CNS.Adv Drug Deliv Rev 45: 295–307, 2000.PubMedCrossRefGoogle Scholar
  23. 23.
    Löscher W, Potschka H. Role of multidrug transporters in pharmacoresistance to antiepileptic drugs.J Pharmacol Exp Ther 301: 7–14, 2002.PubMedCrossRefGoogle Scholar
  24. 24.
    Pardridge WM, Golden PL, Kang YS, Bickel U. Brain microvascular and astrocyte localization of P-glycoprotein.J Neurochem 68: 1278–1285, 1997.PubMedCrossRefGoogle Scholar
  25. 25.
    Golden PL, Pardridge WM. P-Glycoprotein on astrocyte foot processes of unfixed isolated human brain capillaries.Brain Res 819: 143–146, 1999.PubMedCrossRefGoogle Scholar
  26. 26.
    Golden PL, Pardridge WM. Brain microvascular P-glycoprotein and a revised model of multidrug resistance in brain.Cell Mol Neurobiol 20: 165–181, 2000.PubMedCrossRefGoogle Scholar
  27. 27.
    Abbott NJ, Khan EU, Rollinson CMS, Reichel A, Janigro D, Dombrowski SM, Dobbie MS, Begley DJ. Drug resistance in epilepsy: the role of the blood-brain barrier. In: Mechanisms of drug resistance in epilepsy. Lessons from oncology (Ling V, ed), pp 38–47. Chichester: Wiley, Ltd., 2002.CrossRefGoogle Scholar
  28. 28.
    O’Brien JP, Cordon-Cardo C. P-glycoprotein expression in normal human tissues. In: Multidrug resistance in cancer cellls (Gupta S, Tsuruo T, eds), pp 285–291. Chichester: Wiley, Ltd., 1996.Google Scholar
  29. 29.
    Scheffer GL, Scheper RJ. Drug resistance molecules: lessons from oncology.Novartis Found Symp 243: 19–31, 2002.PubMedCrossRefGoogle Scholar
  30. 30.
    Schlachetzki F, Pardridge WM. P-glycoprotein and caveolin-1alpha in endothelium and astrocytes of primate brain.Neuroreport 14: 2041–2046, 2003.PubMedCrossRefGoogle Scholar
  31. 31.
    Marroni M, Marchi N, Cucullo L, Abbott NJ, Signorelli K, Janigro D. Vascular and parenchymal mechanisms in multiple drug resistance: a lesson from human epilepsy.Curr Drug Targets 4: 297–304, 2003.PubMedCrossRefGoogle Scholar
  32. 32.
    Sisodiya SM. Mechanisms of antiepileptic drug resistance.Curr Opin Neurol 16: 197–201, 2003.PubMedCrossRefGoogle Scholar
  33. 32a.
    Volk H, Potschka H, Löscher W. Immunohistochemical localization of p-glycoprotein in rat brain and detection of its increased expression by seizures are sensitive to fixation and staining variables.J Histochem Cytochem, in press.Google Scholar
  34. 33.
    Volk HA, Burkhardt K, Potschka H, Chen J, Becker A, Löscher W. Neuronal expression of the drug efflux transporter P-glycoprotein in the rat hippocampus after limbic seizures.Neuroscience 123: 751–759, 2004.PubMedCrossRefGoogle Scholar
  35. 34.
    Borst P, Evers R, Kool M, Wijnholds J. A family of drug transporters: the multidrug resistance-associated proteins.J Natl Cancer Inst 92: 1295–1302, 2000.PubMedCrossRefGoogle Scholar
  36. 35.
    Seelig A, Blatter XL, Wohnsland F. Substrate recognition by P-glycoprotein and the multidrug resistance-associated protein MRP1: a comparison.Int J Clin Pharmacol Ther 38: 111–121, 2000.PubMedGoogle Scholar
  37. 36.
    Borst P, Evers R, Kool M, Wijnholds J. The multidrug resistance protein family.Biochim Biophys Acta 1461: 347–357, 1999.PubMedCrossRefGoogle Scholar
  38. 37.
    Zhang Y, Han H, Elmquist WF, Miller DW. Expression of various multidrug resistance-associated protein (MRP) homologues in brain microvessel endothelial cells.Brain Res 876: 148–153, 2000.PubMedCrossRefGoogle Scholar
  39. 38.
    Miller DS, Nobmann SN, Gutmann H, Toeroek M, Drewe J, Flicker G. Xenobiotic transport across isolated brain microvessels studied by confocal microscopy.Mol Pharmacol 58: 1357–1367, 2000.PubMedGoogle Scholar
  40. 39.
    Dombrowski SM, Desai SY, Marroni M, Cucullo L, Goodrich K, Bingaman W, Mayberg MR, Bengez L, Janigro D. Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy.Epilepsia 42: 1501–1506, 2001.PubMedCrossRefGoogle Scholar
  41. 40.
    Decleves X, Regina A, Laplanche JL, Roux F, Boval B, Launay JM, Scherrmann JM. Functional expression of P-glycoprotein and multidrug resistance-associated protein (Mrp1) in primary cultures of rat astrocytes.J Neurosci Res 60: 594–602, 2000.PubMedCrossRefGoogle Scholar
  42. 41.
    Rao VV, Dahlheimer JL, Bardgett ME, Snyder AZ, Finch RA, Sartorelli AC, Piwnica-Worms D. Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier.Proc Natl Acad Sci USA 96: 3900–3905, 1999.PubMedCrossRefGoogle Scholar
  43. 42.
    Choudhuri S, Cherrington NJ, Li N, Klaassen CD. Constitutive expression of various xenobiotic and endobiotic transporter mRNAs in the choroid plexus of rats.Drug Metab Dispos 31: 1337–1345, 2003.PubMedCrossRefGoogle Scholar
  44. 43.
    Hirrlinger J, Konig J, Dringen R. Expression of mRNAs of multidrug resistance proteins (Mrps) in cultured rat astrocytes, oligo-dendrocytes, microglial cells and neurones.J Neurochem 82: 716–719, 2002.PubMedCrossRefGoogle Scholar
  45. 44.
    Sun H, Johnson DR, Finch RA, Sartorelli AC, Miller DW, Elmquist WF. Transport of fluorescein in MDCKII-MRP1 transfected cells and mrpl-knockout mice.Biochem Biophys Res Commun 284: 863–869, 2001.PubMedCrossRefGoogle Scholar
  46. 45.
    Wijnholds J, deLange EC, Scheffer GL, van den Berg DJ, Mol CA, van der Valk M, Schinkel AH, Scheper RJ, Breimer DD, Borst P. Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier.J Clin Invest 105: 279–285, 2000.PubMedCrossRefGoogle Scholar
  47. 46.
    Koopen NR, Wolters H, Havinga R, Vonk RJ, Jansen PL, Muller M, Kuipers F. Impaired activity of the bile canalicular organic anion transporter (Mrp2/cmoat) is not the main cause of ethinylestradiol-induced cholestasis in the rat.Hepatology 27: 537–545, 1998.PubMedCrossRefGoogle Scholar
  48. 47.
    Gutmann H, Torok M, Flicker G, Huwyler J, Beglinger C, Drewe J. Modulation of multidrug resistance protein expression in porcine brain capillary endothelial cells in vitro.Drug Metab Dispos 27: 937–941, 1999.PubMedGoogle Scholar
  49. 48.
    Potschka H, Löscher W. Multidrug resistance-associated protein is involved in the regulation of extracellular levels of phenytoin in the brain.Neuroreport 12: 2387–2389, 2001.PubMedCrossRefGoogle Scholar
  50. 49.
    Potschka H, Fedrowitz M, Löscher W. P-glycoprotein and multidrug resistance-associated protein are involved in the regulation of extracellular levels of the major antiepileptic drug carbamazepine in the brain.Neuroreport 12: 3557–3560, 2001.PubMedCrossRefGoogle Scholar
  51. 50.
    Potschka H, Fedrowitz M, Löscher W. Multidrug resistance protein MRP2 contributes to blood-brain barrier function and restricts antiepileptic drug activity.J Pharmacol Exp Ther 306: 124–131, 2003.PubMedCrossRefGoogle Scholar
  52. 51.
    Eisenblatter T, Huwel S, Galla HJ. Characterisation of the brain multidrug resistance protein (BMDP/ABCG2/BCRP) expressed at the blood-brain barrier.Brain Res 971: 221–231, 2003.PubMedCrossRefGoogle Scholar
  53. 52.
    Cistemino S, Mercier C, Bourasset F, Roux F, Scherrmann JM. Expression, up-regulation, and transport activity of the multidrug-resistance protein Abcg2 at the mouse blood-brain barrier.Cancer Res 64: 3296–3301, 2004.CrossRefGoogle Scholar
  54. 53.
    Cooray HC, Blackmore CG, Maskell L, Barrand MA. Localisation of breast cancer resistance protein in microvessel endothelium of human brain.Neuroreport 13: 2059–2063, 2002.PubMedCrossRefGoogle Scholar
  55. 54.
    Seelig A. How does P-glycoprotein recognize its substrates?Int J Clin Pharmacol Ther 36: 50–54, 1998.PubMedGoogle Scholar
  56. 55.
    Neyfakh AA. Mystery of multidrug transporters: the answer can be simple.Med Microbiol 44: 1123–1130, 2002.Google Scholar
  57. 56.
    Stouch TR, Gudmundsson O. Progress in understanding the structure-activity relationships of P-glycoprotein.Adv Drug Deliv Rev 54: 315–328, 2002.PubMedCrossRefGoogle Scholar
  58. 57.
    Haimeur A, Conseil G, Deeley RG, Cole SP. The MRP-related and BCRP/ABCG2 multidrug resistance proteins: biology, substrate specificity and regulation.Curr Drug Metab 5: 21–53, 2004.PubMedCrossRefGoogle Scholar
  59. 58.
    Löscher W. Current status and future directions in the pharmacotherapy of epilepsy.Trends Pharmacol Sci 23: 113–118, 2002.PubMedCrossRefGoogle Scholar
  60. 59.
    Jansen G, Scheper RJ, Dijkmans BA. Multidrug resistance proteins in rheumatoid arthritis, role in disease-modifying antirheumatic drug efficacy and inflammatory processes: an overview.Scand J Rheumatol 32: 325–336, 2003.PubMedCrossRefGoogle Scholar
  61. 60.
    Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression.Psychiatr Clin North Am 19: 179–200, 1996.PubMedCrossRefGoogle Scholar
  62. 61.
    Hellewell JS. Treatment-resistant schizophrenia: reviewing the options and identifying the way forward.J Clin Psychiatry 60[Suppl 23]: 14–19, 1999.PubMedGoogle Scholar
  63. 62.
    Kwan P, Brodie MJ. Early identification of refractory epilepsy.N Engl J Med 342: 314–319, 2000.PubMedCrossRefGoogle Scholar
  64. 63.
    Tishler DM, Weinberg KT, Hinton DR, Barbara N, Annett GM, Raffel C. MDR1 gene expression in brain of patients with medically intractable epilepsy.Epilepsia 36: 1–6, 1995.PubMedCrossRefGoogle Scholar
  65. 64.
    Duncan R, Todd N. Epilepsy and the blood-brain barrier.Br J Hosp Med 45: 32–34, 1991.PubMedGoogle Scholar
  66. 65.
    Sisodiya SM, Lin WR, Harding BN, Squier MV, Thorn M. Drug resistance in epilepsy: expression of drug resistance proteins in common causes of refractory epilepsy.Brain 125: 22–31, 2002.PubMedCrossRefGoogle Scholar
  67. 66.
    Sisodiya SM, Heffeman J, Squier MV. Over-expression of P-glycoprotein in malformations of cortical development.Neuroreport 10: 3437–3441, 1999.PubMedCrossRefGoogle Scholar
  68. 67.
    Aronica E, Goiter JA, Jansen GH, van Veelen CW, van Rijen PC, Leenstra S, Ramkema M, Scheffer GL, Scheper RJ, Troost D. Expression and cellular distribution of multidrug transporter proteins in two major causes of medically intractable epilepsy: focal cortical dysplasia and glioneuronal tumors.Neuroscience 118: 417–429, 2003.PubMedCrossRefGoogle Scholar
  69. 68.
    Aronica E, Goiter JA, Ramkema M, Redeker S, Ozbas-Gercerer F, van Vliet EA, Scheffer GL, Scheper RJ, van d, V, Baayen JC, Troost D. Expression and cellular distribution of multidrug resistance-related proteins in the hippocampus of patients with mesial temporal lobe epilepsy.Epilepsia 45: 441–451, 2004.PubMedCrossRefGoogle Scholar
  70. 69.
    Zhang L, Ong WY, Lee T. Induction of P-glycoprotein expression in astrocytes following intracerebroventricular kainate injections.Exp Brain Res 126: 509–516, 1999.PubMedCrossRefGoogle Scholar
  71. 70.
    Seegers U, Potschka H, Löscher W. Transient increase of P-glycoprotein expression in endothelium and parenchyma of limbic brain regions in the kainate model of temporal lobe epilepsy.Epilepsy Res 51: 257–268, 2002.PubMedCrossRefGoogle Scholar
  72. 71.
    Volk HA, Potschka H, Löscher W. Increased expression of the multidrug transporter P-glycoprotein in limbic brain regions after amygdala-kindled seizures in rats.Epilepsy Res 58: 67–79, 2004.PubMedCrossRefGoogle Scholar
  73. 72.
    Sisodiya SM, Lin WR, Squier MV, Thorn M. Multidrug-resistance protein 1 in focal cortical dysplasia.Lancet 357: 42–43, 2001.PubMedCrossRefGoogle Scholar
  74. 73.
    Sisodiya SM, Martinian L, Scheffer GL, van der Valk D, Cross JH, Scheper RJ, Harding BN, Thom M. Major vault protein, a marker of drug resistance, is upregulated in refractory epilepsy.Epilepsia 44: 1388–1396, 2003.PubMedCrossRefGoogle Scholar
  75. 74.
    Regesta G, Tanganelli P. Clinical aspects and biological bases of drug-resistant epilepsies.Epilepsy Res 34: 109–122, 1999.PubMedCrossRefGoogle Scholar
  76. 75.
    Kerb R, Hoffmeyer S, Brinkmann U. ABC drug transporters: hereditary polymorphisms and pharmacological impact in MDR1, MRP1 and MRP2.Pharmacogenomics 2: 51–64, 2001.PubMedCrossRefGoogle Scholar
  77. 76.
    Siddiqui A, Kerb R, Weale ME, Brinkmann U, Smith A, Goldstein DB, Wood NW, Sisodiya SM. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1.N Engl J Med 348: 1442–1448, 2003.PubMedCrossRefGoogle Scholar
  78. 77.
    Lazarowski A, Sevlever G, Taratuto A, Massaro M, Rabinowicz A. Tuberous sclerosis associated with MDR1 gene expression and drug-resistant epilepsy.Pediatr Neurol 21: 731–734, 1999.PubMedCrossRefGoogle Scholar
  79. 78.
    Potschka H, Fedrowitz M, Löscher W. Brain access and anticonvulsant efficacy of carbamazepine, lamotrigine, and felbamate in ABCC2/MRP2-deficient TR-rats.Epilepsia 44: 1479–1486, 2003.CrossRefPubMedGoogle Scholar
  80. 79.
    Seegers U, Potschka H, Löscher W. Lack of effects of prolonged treatment with phenobarbital or phenytoin on the expression of P-glycoprotein in various rat brain regions.Eur J Pharmacol 451: 149–155, 2002.PubMedCrossRefGoogle Scholar
  81. 80.
    Rizzi M, Caccia S, Guiso G, Richichi C, Goiter JA, Aronica E, Aliprandi M, Bagnati R, Fanelli R, D’Incalci M, Samanin R, Vezzani A. Limbic seizures induce P-glycoprotein in rodent brain: functional implications for pharmacoresistance.J Neurosci 22: 5833–5839, 2002.PubMedGoogle Scholar
  82. 81.
    Löscher W, Volk H, Brandt C, Potschka H. The multidrug transporter P-glycoprotein is overexpressed in limbic brain regions of pharmacoresistant epileptic rats. Program No. 906.2, 2004 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2004. Online.Google Scholar
  83. 82.
    Potschka H, Volk HA, Löscher W. Pharmacoresistance and expression of multidrug transporter P-glycoprotein in kindled rats. Neuroreport 15: 1657–1661, 2004.PubMedCrossRefGoogle Scholar
  84. 83.
    Löscher W. Animal models of drug-resistant epilepsy.Novartis Found Symp 243: 149–159; discussion 159–166, 2002.PubMedCrossRefGoogle Scholar
  85. 84.
    Potschka H, Baltes S, Löscher W. Inhibition of multidrug transporters by verapamil or probenecid does not alter blood-brain barrier penetration of levetiracetam in rats.Epilepsy Res 58: 85–91, 2004.PubMedCrossRefGoogle Scholar
  86. 85.
    Remy S, Gabriel S, Urban BW, Dietrich D, Lehmann TN, Elger CE, Heinemann U, Beck H. A novel mechanism underlying drug resistance in chronic epilepsy.Ann Neurol 53: 469–479, 2003.PubMedCrossRefGoogle Scholar
  87. 86.
    Gilliam F, Hecimovic H, Sheline Y. Psychiatric comorbidity, health, and function in epilepsy.Epilepsy Behav Suppl 4: S26-S30, 2003.CrossRefGoogle Scholar
  88. 87.
    Uhr M, Steckler T, Yassouridis A, Holsboer F. Penetration of amitriptyline, but not of fluoxetine, into brain is enhanced in mice with blood-brain barrier deficiency due to mdr1a P-glycoprotein gene disruption.Neuropsychopharmacology 22: 380–387, 2000.PubMedCrossRefGoogle Scholar
  89. 88.
    Uhr M, Grauer MT, Holsboer F. Differential enhancement of antidepressant penetration into the brain in mice with abcb1ab (mdr1ab) P-glycoprotein gene disruption.Biol Psychiatry 54: 840–846, 2003.PubMedCrossRefGoogle Scholar
  90. 89.
    Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions.Nat Med 10: 685–692, 2004.PubMedCrossRefGoogle Scholar
  91. 90.
    Weiss J, Dormann SM, Martin-Facklam M, Kerpen CJ, Ketabi-Kiyanvash N, Haefeli WE. Inhibition of P-glycoprotein by newer antidepressants.J Pharmacol Exp Ther 305: 197–204, 2003.PubMedCrossRefGoogle Scholar
  92. 91.
    Pariante CM, Thomas SA, Lovestone S, Makoff A, Kerwin RW. Do antidepressants regulate how cortisol affects the brain?Psychoneuroendocrinology 29: 423–447, 2004.PubMedCrossRefGoogle Scholar
  93. 92.
    Plotsky PM, Owens MJ, Nemeroff CB. Psychoneuroendocrinology of depression. Hypothalamic-pituitary-adrenal axis.Psychiatr Clin North Am 21: 293–307, 1998.PubMedCrossRefGoogle Scholar
  94. 93.
    Murck H, Song C, Horrobin DF, Uhr M. Ethyl-eicosapentaenoate and dexamethasone resistance in therapy-refractory depression.Int J Neuropsychopharmacol 7: 341–349, 2004.PubMedCrossRefGoogle Scholar
  95. 94.
    Shibayama Y, Ikeda R, Motoya T, Yamada K. St. John’s Wort (Hypericum perforatum) induces overexpression of multidrug resistance protein 2 (MRP2) in rats: a 30-day ingestion study.Food Chem Toxicol 42: 995–1002, 2004.PubMedCrossRefGoogle Scholar
  96. 95.
    Bart J, Groen HJ, Hendrikse NH, van der Graaf WT, Vaalburg W, de Vries EG. The blood-brain barrier and oncology: new insights into function and modulation.Cancer Treat Rev 26: 449–462, 2000.PubMedCrossRefGoogle Scholar
  97. 96.
    Fellner S, Bauer B, Miller DS, Schaffrik M, Fankhanel M, Spruss T, Bernhardt G, Graeff C, Farber L, Gschaidmeier H, Buschauer A, Flicker G. Transport of paclitaxel (Taxol) across the blood-brain barrier in vitro and in vivo.J Clin Invest 110: 1309–1318, 2002.PubMedGoogle Scholar
  98. 97.
    Thomas SA. Anti-HIV drug distribution to the central nervous system.Curr Pharm Des 10: 1313–1324, 2004.PubMedCrossRefGoogle Scholar
  99. 98.
    Kim RB. Drug transporters in HIV therapy.Top HIV Med 11: 136–139, 2003.PubMedGoogle Scholar
  100. 99.
    Kim RB, Fromm MF, Wandel C, Leake B, Wood AJ, Roden DM, Wilkinson GR. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors.J Clin Invest 101: 289–294, 1998.PubMedCrossRefGoogle Scholar
  101. 100.
    Washington CB, Wiltshire HR, Man M, Moy T, Harris SR, Worth E, Weigl P, Liang Z, Hall D, Marriott L, Blaschke TF. The disposition of saquinavir in normal and P-glycoprotein deficient mice, rats, and in cultured cells.Drug Metab Dispos 28: 1058–1062, 2000.PubMedGoogle Scholar
  102. 101.
    Edwards JE, Brouwer KR, McNamara PJ. GF120918, a P-glycoprotein modulator, increases the concentration of unbound amprenavir in the central nervous system in rats.Antimicrob Agents Chemother 46: 2284–2286, 2002.PubMedCrossRefGoogle Scholar
  103. 102.
    van der Sandt I, Vos CM, Nabulsi L, Blom-Roosemalen MC, Voorwinden HH, de Boer AG, Breimer DD. Assessment of active transport of HIV protease inhibitors in various cell lines and the in vitro blood-brain barrier.AIDS 15: 483–491, 2001.PubMedCrossRefGoogle Scholar
  104. 103.
    Carvey PM. The delivery of drugs to the CNS: Systemic delivery with central action. In: Drug action in the central nervous system (Carvey PM, ed), pp 34–42. New York: Oxford University Press, 1998.Google Scholar
  105. 104.
    Xie R, Hammarlund-Udenaes M, de Boer AG, de Lange EC. The role of P-glycoprotein in blood-brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (−/−) and mdrla (+/+) mice.Br J Pharmacol 128: 563–568, 1999.PubMedCrossRefGoogle Scholar
  106. 105.
    Zong J, Pollack GM. Morphine antinociception is enhanced in mdrla gene-deficient mice.Pharm Res 17: 749–753, 2000.PubMedCrossRefGoogle Scholar
  107. 106.
    Thompson SJ, Koszdin K, Bernards CM. Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein.Anesthesiology 92: 1392–1399, 2000.PubMedCrossRefGoogle Scholar
  108. 107.
    Letrent SP, Pollack GM, Brouwer KR, Brouwer KL. Effects of a potent and specific P-glycoprotein inhibitor on the blood-brain barrier distribution and antinociceptive effect of morphine in the rat.Drug Metab Dispos 27: 827–834, 1999.PubMedGoogle Scholar
  109. 108.
    King M, Su W, Chang A, Zuckerman A, Pasternak GW. Transport of opioids from the brain to the periphery by P-glycoprotein: peripheral actions of central drugs.Nat Neurosci 4: 268–274, 2001.PubMedCrossRefGoogle Scholar
  110. 109.
    Dagenais C, Graff CL, Pollack GM. Variable modulation of opioid brain uptake by P-glycoprotein in mice.Biochem Pharmacol 67: 269–276, 2004.PubMedCrossRefGoogle Scholar
  111. 110.
    Upton RN. Theoretical aspects of P-glycoprotein mediated drug efflux on the distribution volume of anaesthetic-related drugs in the brain.Anaesth Intensive Care 30: 183–191, 2002.PubMedGoogle Scholar
  112. 111.
    Pallis M, Turzanski J, Higashi Y, Russell N. P-glycoprotein in acute myeloid leukaemia: therapeutic implications of its association with both a multidrug-resistant and an apoptosis-resistant phenotype.Leuk Lymphoma 43: 1221–1228, 2002.PubMedCrossRefGoogle Scholar
  113. 112.
    Gennuso F, Femetti C, Tirolo C, Testa N, L’Episcopo F, Caniglia S, Morale MC, Ostrow JD, Pascolo L, Tiribelli C, Marchetti B. Bilirubin protects astrocytes from its own toxicity by inducing up-regulation and translocation of multidrug resistance-associated protein 1 (Mrp1).Proc Natl Acad Sci USA 101: 2470–2475, 2004.PubMedCrossRefGoogle Scholar
  114. 113.
    Bates SF, Chen C, Robey R, Kang M, Figg WD, Fojo T. Reversal of multidrug resistance: lessons from clinical oncology.Novartis Found Symp 243: 83–96, 2002.PubMedCrossRefGoogle Scholar
  115. 114.
    Thomas H, Coley HM. Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein.Cancer Control 10: 159–165, 2003.PubMedGoogle Scholar
  116. 115.
    Doyle LA, Ross DD. Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2).Oncogene 22: 7340–7358, 2003.PubMedCrossRefGoogle Scholar
  117. 115.
    Tan B, Piwnica-Worms D, Ratner L. Multidrug resistance transporters and modulation.Curr Opin Oncol 12: 450–458, 2000.PubMedCrossRefGoogle Scholar
  118. 116.
    Huwyler J, Cerletti A, Fricker G, Eberle AN, Drewe J. By-passing of P-glycoprotein using immunoliposomes.J Drug Target 10: 73–79, 2002.PubMedCrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc 2005

Authors and Affiliations

  1. 1.Department of Pharmacology, Toxicology and PharmacyUniversity of Veterinary Medicine Hannover, FoundationHannoverGermany

Personalised recommendations