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Clinical Pharmacokinetics

, Volume 41, Issue 2, pp 81–92 | Cite as

The Impact of Efflux Transporters in the Brain on the Development of Drugs for CNS Disorders

  • Eve M. TaylorEmail author
Leading Article

Abstract

The development of drugs to treat disorders of the CNS requires consideration of achievable brain concentrations. Factors that influence the brain concentrations of drugs include the rate of transport into the brain across the blood-brain barrier (BBB), metabolic stability of the drug, and active transport out of the brain by efflux mechanisms. To date, three classes of transporter have been implicated in the efflux of drugs from the brain: multidrug resistance transporters, monocarboxylic acid transporters, and organic ion transporters. Each of the three classes comprises multiple transporters, each of which has multiple substrates, and the combined substrate profile of these transporters includes a large number of commonly used drugs. This system of transporters may therefore provide a mechanism through which the penetration of CNS-targeted drugs into the brain is effectively minimised. The action of these efflux transporters at the BBB may be reflected in the clinic as the minimal effectiveness of drugs targeted at CNS disorders, including HIV dementia, epilepsy, CNS-based pain, meningitis and brain cancers. Therefore, modulation of these efflux transporters by design of inhibitors and/or design of compounds that have minimal affinity for these transporters may well enhance the treatment of intractable CNS disorders.

Keywords

Quinidine Ivermectin Efflux Transporter Organic Anion Transporter Brain Capillary Endothelial Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

The author would like to thank Drs Scott Wieland, Michelle Glasky and Mark Foreman for helpful comments on this manuscript, and Ben Aguillon for excellent assistance with graphic art.

References

  1. 1.
    Kandel ER, Schwartz JH, Jessell TM, editors. Principles of neural science. 4th ed. New York: McGraw-Hill, 2000: 1294Google Scholar
  2. 2.
    Pappenheimer JR, Heisey SR, Jordan EF. Active transport of diodrast and phenolsulfonphthalein from cerebrospinal fluid to blood. Am J Physiol 1961; 200: 1–10PubMedGoogle Scholar
  3. 3.
    Schanker LS, Prockop LD, Schou J, et al. Rapid efflux of some quaternary ammonium compounds from cerebrospinal fluid. Life Sci 1962; 10: 515–21CrossRefGoogle Scholar
  4. 4.
    Coben LA, Loeffier JD, Elsasser JC. Spinal fluid iodide transport in dog. Am J Physiol 1964; 206: 1373–8PubMedGoogle Scholar
  5. 5.
    Davson H, Pollay M. Influence of various drugs on the transport of 131I and PAH across the cerebrospinal fluid-blood barrier. J Physiol 1964; 167: 239–46Google Scholar
  6. 6.
    Reed DJ, Woodbury DM, Jacobs L, et al. Factors affecting distribution of iodide in brain and cerebrospinal fluid. Am J Physiol 1965; 209: 757–65PubMedGoogle Scholar
  7. 7.
    Cserr H. Potassium exchange between cerebrospinal fluid, plasma and brain. Am J Physiol 1965; 209: 1219–26PubMedGoogle Scholar
  8. 8.
    Katzman R, Graziani L, Kaplan R, et al. Exchange of cerebrospinal fluid potassium with blood and brain. Study in normal and Ouabain perfused cats. Arch Neurol 1965; 13: 513–24PubMedCrossRefGoogle Scholar
  9. 9.
    Fishman RA. Blood-brain and CSF barriers to penicillin and related organic acids. Arch Neurol 1966; 15: 113–24PubMedCrossRefGoogle Scholar
  10. 10.
    Banks WA. Physiology and pathology of the blood-brain barrier: implication for microbial pathogenesis, drug delivery and neurodegenerative disorders. J Neurovirol 1999; 5: 538–55PubMedCrossRefGoogle Scholar
  11. 11.
    Adkison KDK, Artru AA, Poweres KM, et al. Contribution of probenecid-sensitive anion transport processes at the brain capillary endothelium and choroid plexus to the efficient efflux of valproic acid from the central nervous system. J Pharmacol Exp Ther 1994; 268: 797–805PubMedGoogle Scholar
  12. 12.
    Adkison KDK, Powers KM, Artru AA, et al. Effect of paraaminohippurate on the efflux of valproic acid from the central nervous system of the rabbit. Epilepsy Res 1996; 23: 95–104PubMedCrossRefGoogle Scholar
  13. 13.
    Cornford EM, Diep CP, Pardridge WM. Blood-brain barrier transport of valproic acid. J Neurochem 1985; 44: 1541–50PubMedCrossRefGoogle Scholar
  14. 14.
    Deguchi Y, Nozawa K, Yamada S, et al. Quantitative evaluation of brain distribution and blood-brain barrier efflux transport of probenecid in rats by microdialysis: possible involvement of the monocarboxylic acid transport system. J Pharmacol Exp Ther 1997; 280: 551–60PubMedGoogle Scholar
  15. 15.
    Deguchi Y, Yokoyama Y, Sakamoto T, et al. Brain distribution of mercaptopurine is regulated by the efflux transport system in the blood-brain barrier. Life Sci 1997; 66: 649–62CrossRefGoogle Scholar
  16. 16.
    Doze P, Van Waarde A, Eisinga PH, et al. Enhanced cerebral uptake of receptor ligands by modulation of P-glycoprotein function in the blood-brain barrier. Synapse 2000; 36: 66–74PubMedCrossRefGoogle Scholar
  17. 17.
    Galinsky RE, Flaharty KK, Hoesterey BL, et al. Probenecid enhances central nervous system uptake of 2′,3′-dideoxyinosine by inhibiting cerebrospinal fluid efflux. J Pharmacol Exp Ther 1991; 257: 972–8PubMedGoogle Scholar
  18. 18.
    Hedaya MA, Sawchuk RJ. Effect of probenecid on the renal and nonrenal clearances of zidovudine and its distribution into cerebrospinal fluid in the rabbit. J Pharm Sci 1989; 78: 716–22PubMedCrossRefGoogle Scholar
  19. 19.
    Ooie T, Terasaki T, Suzuki H, et al. Kinetic evidence for active efflux transport across the blood-brain barrier of quinolone antibiotics. J Pharmacol Exp Ther 1997; 283: 293–304PubMedGoogle Scholar
  20. 20.
    Spector R, Lorenzo AV. The effects of salicylate and probenecid of the cerebrospinal fluid transport of penicillin, aminosalicylic acid and iodide. J Pharmacol Exp Ther 1974; 188: 55–65PubMedGoogle Scholar
  21. 21.
    Susuki H, Sawada Y, Sugiyama Y, et al. Transport of imipenem, a novel carbapenem antibiotic, in the rat central nervous system. J Pharmacol Exp Ther 1989; 250: 979–84Google Scholar
  22. 22.
    Wang Y, Sawchuk RJ. Zidovudine transport in the rabbit brain during intravenous and intracerebroventricular infusion. J Pharm Sci 1995; 84: 871–6PubMedCrossRefGoogle Scholar
  23. 23.
    Gottesman MM, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 1993; 62: 385–427PubMedCrossRefGoogle Scholar
  24. 24.
    Gottesman MM, Pastan I, Ambudkar SV. P-glycoprotein and multidrug resistance. Curr Opin Genet Dev 1996; 6: 610–7PubMedCrossRefGoogle Scholar
  25. 25.
    Cordon-Cardo C, O’Brien JP, Casal D, et al. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 1989; 86: 695–8PubMedCrossRefGoogle Scholar
  26. 26.
    Cordon-Cardo C, O’Brien JP, Boccia J, et al. Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J Histochem Cytochem 1990; 38: 1277–87PubMedCrossRefGoogle Scholar
  27. 27.
    Thiebaut F, Tsuro T, Hamada H, et al. 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 1989; 37: 159–64PubMedCrossRefGoogle Scholar
  28. 28.
    Tishler DM, Weinberg KI, Hinton DR, et al. MDRl gene expression in brain of patients with medically intractable epilepsy. Epilepsia 1995; 36: 1–6PubMedCrossRefGoogle Scholar
  29. 29.
    Sugawara I, Hamada H, Tsuro T, et al. Specialized localization of P-glycoprotein recognized by MRK16 monoclonal antibody in endothelial cells of the brain and spinal cord. Jpn J Cancer Res 1990; 81: 727–30PubMedCrossRefGoogle Scholar
  30. 30.
    Schumacher U, Mollgard K. The multidrug-resistance P-glycoprotein (P-gp, mdr1) is an early marker of blood-brain barrier development in the microvessels of the developing human brain. Histochem Cell Biol 1997; 108: 179–82PubMedCrossRefGoogle Scholar
  31. 31.
    Pardridge WM, Golden PL, Kang Y-S, et al. Brain microvascular and astrocyte localization of P-glycoprotein. J Neurochem 1997; 68: 1278–85PubMedCrossRefGoogle Scholar
  32. 32.
    Jette L, Tetu B, Beliveau R. High levels of p-glycoprotein detected in isolated brain capillaries. Biochim Biophys Acta 1993; 1150: 147–54PubMedCrossRefGoogle Scholar
  33. 33.
    Jette L, Pouloit J-F, Murphy G, et al. Isoform 1 (mdr3) is the major form of p-glycoprotein expressed in mouse brain capillaries. Biochem J 1995; 305: 761–6PubMedGoogle Scholar
  34. 34.
    Sugawara I, Akiyama S, Scheper RJ, et al. Lung resistance protein (LRP) expression in human normal tissues in comparison with that of MDR1 and MRP. Cancer Lett 1997; 112: 23–31PubMedCrossRefGoogle Scholar
  35. 35.
    Seetharaman S, Barrand MA, Maskell L, et al. Multidrug resistance-related transport proteins in isolated human brain microvessels and in cells cultured from these isolates. J Neurochem 1998; 70: 1151–9PubMedCrossRefGoogle Scholar
  36. 36.
    Rao VV, Dahlheimer JL, Bardgett ME, et al. Choroid plexus epithelial expression of mdr1 P-glycoprotein and multidrug resistance-associated protein contributes to the blood-cere-brospinal-fluid drug-permeability barrier. Proc Natl Acad Sci USA 1999; 96: 3900–5PubMedCrossRefGoogle Scholar
  37. 37.
    Toth K, Vaughn MM, Peress NS, et al. MDR1 P-glycoprotein is expressed by endothelial cells of newly formed capillaries in human gliomas but is not expressed in the neovasculature of other primary tumors. Am J Pathol 1996; 149: 853–8PubMedGoogle Scholar
  38. 38.
    Beaulieau E, Demeule M, Pouliot J-F, et al. P-gp of blood-brain barrier: cross-reactivity of Mab C219 with a 190kDa protein in bovine and rat isolated brain capillaries. Biochim Biophys Acta 1995; 1233: 27–32CrossRefGoogle Scholar
  39. 39.
    Barrand MA, Robertson KJ, von Weikersthal SF. Comparisons of P-glycoprotein expression in isolated rat brain micro-vessels and in primary cultures of endothelial cells derived from microvasculature of rat brain, epidymal fat pad and from aorta. FEBS Lett 1995; 374: 179–83PubMedCrossRefGoogle Scholar
  40. 40.
    Begley DJ, Lechardeur D, Chen Z-D, et al. Functional expression of P-glycoprotein in an immortalized cell line of rat brain endothelial cells, RBE4. J Neurochem 1996; 67: 988–5PubMedCrossRefGoogle Scholar
  41. 41.
    Beaulieu E, Demeule M, Ghitescu L, et al. P-glycoprotein is strongly expressed in the luminal membranes of the endo-thelium of blood vessels in the brain. Biochem J 1997; 326: 539–44PubMedGoogle Scholar
  42. 42.
    Decleves X, Regina A, Laplanche J-L, et al. Functional expression of P-glycoprotein and multidrug resistance-associated protein (Mrp1) in primary cultures of rat astrocytes. J Neurosci Res 2000; 60: 594–601PubMedCrossRefGoogle Scholar
  43. 43.
    Matsuoka Y, Okazaki M, Kitamura Y, et al. Developmental expression of P-glycoprotein (multidrug resistance gene product) in rat brain. J Neurobiol 1999; 39: 383–92PubMedCrossRefGoogle Scholar
  44. 44.
    Stewart PA, Beliveau R, Rogers KA. Cellular localization of P-glycoprotein in brain versus gonadal capillaries. J Histochem Cytochem 1996; 44: 679–85PubMedCrossRefGoogle Scholar
  45. 45.
    Regina A, Koman A, Piciotti M, et al. Mrp1 multidrug resistance-associated protein and p-glycoprotein expression in rat brain microvessel endothelial cells. J Neurochem 1998; 71: 705–15PubMedCrossRefGoogle Scholar
  46. 46.
    Croop JM, Raymond M, Haber D, et al. The three mouse multidrug resistance (mdr) genes are expressed in a tissue-specific manner in normal mouse tissues. Mol Cell Biol 1989; 9: 1346–50PubMedGoogle Scholar
  47. 47.
    Hegmann EJ, Bauer HC, Kerbel RS. Expression and functional activity of p-glycoprotein in cultured cerebral capillary endothelial cells. Cancer Res 1992; 52: 6969–75PubMedGoogle Scholar
  48. 48.
    Tatsuta T, Naito M, Oh-hara T, et al. Functional involvement of p-glycoprotein in blood-brain barrier. J Biol Chem 1992; 267: 20383–91PubMedGoogle Scholar
  49. 49.
    Qin Y, Sato TN. Mouse multidrug resistance 1a/3 gene is the earliest known endothelial cell differentiation marker during blood-brain barrier development. Dev Dyn 1995; 202: 172–80PubMedCrossRefGoogle Scholar
  50. 50.
    Tsuji A, Terasaki T, Takabatake Y, et al. P-glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells. Life Sci 1992; 51: 1427–37PubMedCrossRefGoogle Scholar
  51. 51.
    Zhang Y, Han H, Elmquist WF, et al. Expression of various multidrug resistance-associated protein (MRP) homologues in brain microvessel endothelial cells. Brain Res 2000; 876: 148–53PubMedCrossRefGoogle Scholar
  52. 52.
    Lechardeur D, Scherman D. Functional expression of the p-glycoprotein mdr in primary cultures of bovine cerebral endothelial cells. Cell Biol Toxciol 1995; 11: 283–93CrossRefGoogle Scholar
  53. 53.
    Bradley G, Georges E, Ling V. Sex-dependent and independent expression of the p-glycoprotein isoforms in Chinese hamster. J Cell Physiol 1990; 145: 398–408PubMedCrossRefGoogle Scholar
  54. 54.
    Warren KE, Patel MC, McCully CM, et al. Effect of P-glycoprotein modulation with cyclosporin on cerebrospinal fluid penetration of doxorubicin in non-human primates. Cancer Chemother Pharmacol 2000; 45: 207–12PubMedCrossRefGoogle Scholar
  55. 55.
    Golden PL, Pardridge WM. Brain microvascular P-glycoprotein and a revised model of multidrug resistance in brain. Cell Mol Neurobiol 2000; 20: 165–81PubMedCrossRefGoogle Scholar
  56. 56.
    Schinkel AH. P-glycoprotein, a gatekeeper in the blood-brain barrier. Adv Drug Deliv Rev 1999; 36: 179–94PubMedCrossRefGoogle Scholar
  57. 57.
    Schinkel AH, Smit JJM, van Teilingen O, et al. Disruption of the mouse mdr1a p-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 1994; 77: 491–502PubMedCrossRefGoogle Scholar
  58. 58.
    Schinkel AH, Wagenaar E, van Deemter L, et al. Absence of the mdr1a p-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest 1995; 96: 1698–705PubMedCrossRefGoogle Scholar
  59. 59.
    Schinkel AH, Wagenaar E, Mol CAAM, et al. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest 1996; 97: 2517–24PubMedCrossRefGoogle Scholar
  60. 60.
    Mayer U, Wagenaar E, Beijnen JH, et al. Substantial excretion of digoxin via the intestinal mucosa and prevention of long-term digoxin accumulation in the brain by the mdrla p-glycoprotein. Br J Pharmacol 1996; 119: 1038–44PubMedCrossRefGoogle Scholar
  61. 61.
    Murata M, Tamai I, Kato H, et al. Efflux transport of a new quinolone antibacterial agent, HSR-903, across the blood-brain barrier. J Pharmacol Exp Ther 1999; 290: 51–7PubMedGoogle Scholar
  62. 62.
    Kim RB, Fromm MF, Wandel C, et al. The drug transporter p-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest 1998; 101: 289–94PubMedCrossRefGoogle Scholar
  63. 63.
    De Graaf D, Sharma RC, Mechetner EB, et al. P-glycoprotein confers methotrexate resistance in 3T6 cells with deficient carrier-mediated methotrexate uptake. Proc Natl Acad Sci USA 1996; 93: 11238–42Google Scholar
  64. 64.
    Sharom FJ. The P-glycoprotein efflux pump: how does it transport drugs? J Membr Biol 1997; 160: 161–75PubMedCrossRefGoogle Scholar
  65. 65.
    Borst P, Evers R, Kool M, et al. The multidrug resistance protein family. Biochim Biophys Acta 1999; 1461: 347–57PubMedCrossRefGoogle Scholar
  66. 66.
    Zaman GJR, Versantvoort CHM, Smit JJM, et al. Analysis of the expression of MRP, the gene for a new putative transmembrane drug transporter, in human multidrug resistant lung cancer cell lines. Cancer Res 1993; 53: 1747–50PubMedGoogle Scholar
  67. 67.
    Stride BD, Valdimarsson G, Gerlach JH, et al. Structure and expression of the messenger RNA encoding the murine multi-drug resistance protein, an ATP-binding cassette transporter. Mol Pharmacol 1996; 49: 962–71PubMedGoogle Scholar
  68. 68.
    Miller DS, Nobmann SN, Gutmann H, et al. Xenobiotic transport across isolated brain microvessels studied by confocal microscopy. Mol Pharmacol 2000; 58: 1357–67PubMedGoogle Scholar
  69. 69.
    Flens MJ, Zaman GJR, van der Valk P, et al. Tissue distribution of the multidrug resistance protein. Am J Pathol 1996; 148: 1237–47PubMedGoogle Scholar
  70. 70.
    Gutmann H, Torok M, Fricker G, et al. Modulation of multidrug resistance protein expression in porcine brain capillary endothelial cells in vitro. Drug Metab Dispos 1999; 27: 937–41PubMedGoogle Scholar
  71. 71.
    Wijnholds J, de Lange ECM, Scheffer GL, et al. Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier. J Clin Invest 2000; 105:279–85PubMedCrossRefGoogle Scholar
  72. 72.
    Huai-Yun H, Secrest DT, Mark KS, et al. Expression of multi-drug resistance-associated protein (MRP) in brain microvessel endothelial cells. Biochem Biophys Res Commun 1998; 243: 816–20PubMedCrossRefGoogle Scholar
  73. 73.
    Kusuhara H, Suzuki H, Naito M, et al. Characterization of efflux transport of organic anions in a mouse brain capillary endothelial cell line. J Pharmacol Exp Ther 1998; 285: 1260–5PubMedGoogle Scholar
  74. 74.
    Nishino J-I, Suzuki H, Sugiyama D, et al. Transepithelial transport of organic anions across the choroid plexus: possible involvement of organic anion transporter and multidrug resistance-associated protein. J Pharmacol Exp Ther 1999; 290: 289–94PubMedGoogle Scholar
  75. 75.
    Wijnholds J, Evers R, van Leusden MR, et al. Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein. Nat Med 1997; 3: 1275–9PubMedCrossRefGoogle Scholar
  76. 76.
    Lorico A, Rappa G, Finch RA, et al. Disruption of the murine MRP (multidrug resistance protein) gene leads to increased sensitivity to etoposide (VP-16) and increased levels of glutathione. Cancer Res 1997; 57: 5238–42PubMedGoogle Scholar
  77. 77.
    Wijnholds J, Scheffer GL, van der Valk M, et al. Multidrug resistance protein 1 protects the oropharyngeal mucosal layer and the testicular tubules against drug-induced damage. J Exp Med 1998; 188: 797–808PubMedCrossRefGoogle Scholar
  78. 78.
    Kool M, de Haas M, Scheffer GL, et al. Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer Res 1997; 57: 3537–47PubMedGoogle Scholar
  79. 79.
    Kool M, van der Linden M, de Haas M, et al. Expression of human MRP6, a homologue of the multidrug resistance protein gene MRP1, in tissues and cancer cells. Cancer Res 1999; 59: 175–82PubMedGoogle Scholar
  80. 80.
    McAleer MA, Breen MA, White NL, et al. PABC11 (also known as MOAT-C and MRP5), a member of the ABC family of proteins, has anion transporter activity but does not confer multidrug resistance when overexpressed in human embryonic kidney 293 cells. J Biol Chem 1999; 274: 23541–8PubMedCrossRefGoogle Scholar
  81. 81.
    Halestrap AP, Price NT. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J 1999; 343: 281–99PubMedCrossRefGoogle Scholar
  82. 82.
    Poole RC, Halestrap AP. Transport of lactate and other monocarboxylates across mammalian membranes. Am J Physiol 1993; 264: C761–82PubMedGoogle Scholar
  83. 83.
    Drewes LR. What is the blood-brain barrier? A molecular perspective. Adv Exp Med Biol 1999; 474: 111–22PubMedCrossRefGoogle Scholar
  84. 84.
    Ackley DC, Yokel RA. Aluminium citrate is transported from brain into blood via the monocarboxylic acid transporter located at the blood-brain barrier. Toxicology 1997; 120: 89–97PubMedCrossRefGoogle Scholar
  85. 85.
    Ackley DC, Yokel RA. Aluminum transport out of brain extracellular fluid is proton dependent and inhibited by mersalyl acid, suggesting mediation by the monocarboxylate transporter (MCT1). Toxicology 1998; 127: 59–67PubMedCrossRefGoogle Scholar
  86. 86.
    Yan R, Taylor EM. AIT-082 is transported out of brain by a saturable mechanism: possible involvement of multidrug resistance and monocarboxylic acid transporters. Drug Metab Dispos. In pressGoogle Scholar
  87. 87.
    Jackson VN, Price NT, Carpenter L, et al. Cloning of the monocarboxylate transporter isoform MCT2 from rat testis provides evidence that expression in tissues is species-specific and may involve post-transcriptional regulation. Biochem J 1997; 324: 447–53PubMedGoogle Scholar
  88. 88.
    Koehler-Stec EM, Simpson IA, Vannucci SJ, et al. Monocarboxylate transporter expression in mouse brain. Am J Physiol 1998; 275 (3 Pt 1): E516–24PubMedGoogle Scholar
  89. 89.
    Price NT, Jackson VN, Halestrap AP. Cloning and sequencing of four new mammalian monocarboxylate transporter (MCT) homologues confirms the existence of a transporter family with an ancient past. Biochem J 1998; 329: 321–8PubMedGoogle Scholar
  90. 90.
    Gerhart DZ, Enerson BE, Zhdankina OY, et al. Expression of monocarboxylate transporter MCT1 by brain endothelium and glia in adult and suckling rats. Am J Physiol 1997; 273 (1 Pt 1): E207–13PubMedGoogle Scholar
  91. 91.
    Takanaga H, Tamai I, Inaba S. DNA cloning and functional characterization of rat intestinal monocarboxylate transporter. Biochem Biophys Res Commun 1995; 217: 370–7PubMedCrossRefGoogle Scholar
  92. 92.
    Leino RL, Gerhart DZ, Drewes LR. Monocarboxylate transporter (MCT1) abundance in brains of suckling and adult rats: a quantitative electron microscopic immunogold study. Brain Res Dev Brain Res 1999; 113: 47–54PubMedCrossRefGoogle Scholar
  93. 93.
    Gerhart DZ, Enerson BE, Zhdankina OY, et al. Expression of the monocarboxylate transporter MCT2 by rat brain glia. Glia 1998; 22: 272–81PubMedCrossRefGoogle Scholar
  94. 94.
    Lafreniere RG, Carrel L, Willard HE A novel transmembrane transporter encoded by the XPCT gene in Xq13.2. Hum Mol Genet 1994; 3: 1133–9PubMedCrossRefGoogle Scholar
  95. 95.
    Koepsell H. Organic cation transporters in intestine, kidney, liver and brain. Annu Rev Physiol 1998; 60: 243–66PubMedCrossRefGoogle Scholar
  96. 96.
    Inui K-I, Masuda S, Saito H. Cellular and molecular aspects of drug transport in the kidney. Kidney Int 2000; 58: 944–58PubMedCrossRefGoogle Scholar
  97. 97.
    Sekine T, Cha SH, Endou H. The multispecific organic anion transporter (OAT) family. Eur J Appl Physiol 2000; 440: 337–50Google Scholar
  98. 98.
    Kusuhara H, Sekine T, Utsunomiya-Tate N, et al. Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain. J Biol Chem 1999; 274: 13675–80PubMedCrossRefGoogle Scholar
  99. 99.
    Hosoyamada M, Sekine T, Kanai Y, et al. Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney. Am J Physiol 1999; 276 (1 Pt 2): F122–8PubMedGoogle Scholar
  100. 100.
    Zhang L, Dresser MJ, Gray AT, et al. Cloning and functional expression of a human liver organic cation transporter. Mol Pharmacol 1997; 51: 913–21PubMedGoogle Scholar
  101. 101.
    Busch AE, Karbach U, Miska D, et al. Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine. Mol Pharmacol 1998; 54: 342–52PubMedGoogle Scholar
  102. 102.
    Grundemann D, Babin-Ebell J, Martel F, et al. Primary structure and functional expression of the apical organic cation transporter from kidney epithelial LLC-PK1 cells. J Biol Chem 1997; 272: 10408–13PubMedCrossRefGoogle Scholar
  103. 103.
    Kekuda R, Prasad PD, Wu X, et al. Cloning and functional characterization of a potential-sensitive, polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta. J Biol Chem 1998; 273: 15971–9PubMedCrossRefGoogle Scholar
  104. 104.
    Wu X, Kekuda R, Huang W, et al. Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain. J Biol Chem 1998; 273: 32776–86PubMedCrossRefGoogle Scholar
  105. 105.
    Angeletti RH, Bergwerk AJ, Novikoff PM, et al. Dichotomous development of the organic anion transport protein in liver and choroid plexus. Am J Physiol 1998; 275: C882–7PubMedGoogle Scholar
  106. 106.
    Angeletti RH, Novikoff PM, Juvvadi SR, et al. The choroid plexus epithelium is the site of the organic anion transport protein in the brain. Proc Natl Acad Sci USA 1997; 94: 283–6PubMedCrossRefGoogle Scholar
  107. 107.
    Noe B, Hagenbuch B, Stieger B, et al. Isolation of a multispecific organic anion and cardiac glycoside transporter from rat brain. Proc Natl Acad Sci USA 1997; 94: 10346–50PubMedCrossRefGoogle Scholar
  108. 108.
    Abe T, Kakyo M, Sakagami H, et al. Molecular characterization and tissue distribution of a new organic anion transporter subtype (oatp3) that transports thyroid hormones and taurocholate and comparison with oatp2. J Biol Chem 1998; 273: 22395–401PubMedCrossRefGoogle Scholar
  109. 109.
    Asaba H, Hosoya K-I, Takanaga H, et al. Blood-brain barrier is involved in the efflux transport of a neuroactive steroid, dehydroepiandrosterone sulfate, via organic anion transporting polypeptide 2. J Neurochem 2000; 75: 1907–16PubMedCrossRefGoogle Scholar
  110. 110.
    Walters HC, Craddock AL, Fusegawa H, et al. Expression, transport properties, and chromosomal location of organic anion transporter subtype 3. Am J Physiol Gastrointest Liver Physiol 2000; 279: G1188–200PubMedGoogle Scholar
  111. 111.
    Tamai I, Yabuuchi H, Nezu J-I, et al. Cloning and characterization of a novel human pH-dependent organic cation transporter, OCTN1. FEBS Lett 1997; 419: 107–11PubMedCrossRefGoogle Scholar
  112. 112.
    Tamai I, Ohashi R, Nezu J-I, et al. Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2. J Biol Chem 1998; 273: 20378–82PubMedCrossRefGoogle Scholar
  113. 113.
    Tamai I, Ohashi R, Nezu J-I, et al. Molecular and functional characterization of organic cation/carnitine transporter family in mice. J Biol Chem 2000; 275: 40064–72PubMedCrossRefGoogle Scholar
  114. 114.
    Wu X, Huang W, Prasad PD, et al. Functional characteristics and tissue distribution pattern of organic cation transporter 2 (OCTN2), an organic cation/carnitine transporter. J Pharmacol Exp Ther 1999; 290: 1482–92PubMedGoogle Scholar
  115. 115.
    Wu X, George RL, Huang W, et al. Structural and functional characteristics and tissue distribution pattern of rat OCTN1, an organic cation transporter, cloned from placenta. Biochim Biophys Acta 2000; 1466: 315–27PubMedCrossRefGoogle Scholar
  116. 116.
    Aggarwal S, Tsuruo T, Gupta S. Altered expression and function of P-glycoprotein (170 kDa) encoded by the MDR 1 gene, in T cell subsets from aging humans. J Clin Immunol 1997; 17: 448–54PubMedCrossRefGoogle Scholar
  117. 117.
    Dixon RL, Owens ES, Rall DP. Evidence of active transport of benzyl-14C-penicillin from cerebrospinal fluid to blood. J Pharm Sci 1969; 58: 1106–9PubMedCrossRefGoogle Scholar
  118. 118.
    Takasawa K, Terasaki T, Suzuki H, et al. In vivo evidence for carrier-mediated efflux transport of 3′-azido-3′-deoxythymidine and 2′,3′-dideoxyinosine across the blood-brain barrier via a probenecid-sensitive transport system. J Pharmacol Exp Ther 1997; 281: 369–75PubMedGoogle Scholar
  119. 119.
    Wong SL, van Belle K, Sawchuk RJ. Distributional transport kinetics of zidovudine between plasma and brain extracellular fluid/cerebrospinal fluid in the rabbit: investigation of the inhibitory effect of probenecid utilizing microdialysis. J Pharmacol Exp Ther 1993; 264: 899–909PubMedGoogle Scholar
  120. 120.
    Wang Y, Wei Y, Sawchuk RJ. Zidovudine transport within the rabbit brain during intracerebroventricular administration and the effect of probenecid. J Pharm Sci 1997; 86: 1484–93PubMedCrossRefGoogle Scholar
  121. 121.
    Dykstra KH, Arya A, Arriola DM, et al. Microdialysis study of zidovudine (AZT) transport in rat brain. J Pharmacol Exp Ther 1993; 267: 1227–36PubMedGoogle Scholar
  122. 122.
    Loscher W, Frey H-H. Transport of GAB A at the blood-CSF interface. J Neurochem 1982; 38: 1072–9PubMedCrossRefGoogle Scholar
  123. 123.
    Spector R, Goetzl EJ. Leukotriene C4 transport and metabolism in the central nervous system. J Neurochem 1986; 46: 1308–12PubMedCrossRefGoogle Scholar
  124. 124.
    Burgio DE, Gosland MP, McNamara PJ. Modulation effects of cyclosporine on etoposide pharmacokinetics and CNS distribution in the rat utilizing microdialysis. Biochem Pharmacol 1996; 51: 987–92PubMedCrossRefGoogle Scholar
  125. 125.
    Drion N, Lemaire M, Lefauconnier J-M, et al. Role of p-glycoprotein in the blood-brain transport of colchicine and vinblastine. J Neurochem 1996; 67: 1688–93PubMedCrossRefGoogle Scholar
  126. 126.
    Desrayaud S, Guntz P, Scherrmann J-M, et al. Effect of the p-glycoprotein inhibitor, SDZ PSC 833, on the blood and brain pharmacokinetics of colchicine. Life Sci 1997; 61: 153–63PubMedCrossRefGoogle Scholar
  127. 127.
    Lemaire M, Bruelisauer A, Guntz P, et al. Dose-dependent brain penetration of SDZ PSC 833, a novel multidrug resistance-reversing cyclosporin, in rats. Cancer Chemother Pharmacol 1996; 38: 481–6PubMedCrossRefGoogle Scholar
  128. 128.
    Mayer U, Wagenaar E, Dorobek B, et al. Full blockade of intestinal P-glycoprotein and extensive inhibition of blood-brain barrier P-glycoprotein by oral treatment of mice with PSC833. J Clin Invest 1997; 100: 2430–6PubMedCrossRefGoogle Scholar
  129. 129.
    Kusuhara H, Suzuki H, Terasaki T, et al. P-glycoprotein mediates the efflux of quinidine across the blood-brain barrier. J Pharmacol Exp Ther 1997; 283: 574–80PubMedGoogle Scholar
  130. 130.
    Didier AD, Loor F. Decreased biotolerability for ivermectin and cyclosporin A in mice exposed to potent P-glycoprotein inhibitors. Int J Cancer 1995; 63: 263–7PubMedCrossRefGoogle Scholar
  131. 131.
    Volm M. Multidrug resistance and its reversal. Anticancer Res 1998; 18: 2905–18PubMedGoogle Scholar
  132. 132.
    Sonneveld P, Wiemer E. Inhibitors of multidrug resistance. Curr Opin Oncol 1997; 9: 543–8PubMedCrossRefGoogle Scholar
  133. 133.
    Rousselle C, Clair P, Lefauconnier J-M, et al. New advances in the transport of doxorubicin through the blood-brain barrier by a peptide vector-mediated strategy. Mol Pharmacol 2000; 57: 679–86PubMedGoogle Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  1. 1.Neo Therapeutics Inc.IrvineUSA

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