The Role of Drug Transporters at the Blood-Brain Barrier

Annual Review of Pharmacology and Toxicology

Volumn 43, Issue , 2003, Pages 629-656

  De Boer, A G ^a   Van der Sandt, I C J ^a   Gaillard, P J ^a  

^a LEIDEN UNIVERSITY   (Netherlands)

Author keywords

Anion transporters; Large amino acid transporters; Multidrug resistance proteins; Nucleoside transporters; P glycoprotein; Scavenger receptors; Transferrin receptor

Indexed keywords

2,4 BIS(ALLYLAMINO) 6 [4 [[2,2 BIS(4 FLUOROPHENYL)ETHYL]AMINO]PIPERIDINO] 1,3,5 TRIAZINE; AMINO ACID TRANSPORTER; AMYLOID BETA PEPTIDE[1-42]; AMYLOID BETA PROTEIN; APOLIPOPROTEIN E; CARRIER PROTEIN; DILTIAZEM; DOXORUBICIN; ELACRIDAR; FLESINOXAN; GLYCOPROTEIN P; MIFEPRISTONE; MORPHINE; MORPHINE 3 GLUCURONIDE; MULTIDRUG RESISTANCE PROTEIN; MULTIDRUG RESISTANCE PROTEIN 5; MULTIDRUG RESISTANCE PROTEIN 6; NUCLEOSIDE TRANSPORTER; ORGANIC ANION TRANSPORTER; PHENYTOIN; SCAVENGER RECEPTOR; TACROLIMUS; TRANSFERRIN 1 RECEPTOR; TRANSFERRIN 2 RECEPTOR; TRANSFERRIN RECEPTOR; UNCLASSIFIED DRUG; UNINDEXED DRUG; VALSPODAR; VERAPAMIL; VINBLASTINE; ZOSUQUIDAR; DRUG;

ACTIVE TRANSPORT; BLOOD BRAIN BARRIER; CAPILLARY PRESSURE; DOSE RESPONSE; DRUG BRAIN LEVEL; DRUG METABOLISM; DRUG PROTEIN BINDING; DRUG TISSUE LEVEL; DRUG TRANSPORT; ENDOCYTOSIS; HOMEOSTASIS; HUMAN; MICRODIALYSIS; NEUROPROTECTION; NONHUMAN; PHARMACODYNAMICS; PINOCYTOSIS; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; REVIEW; SIDE EFFECT; VASCULAR ENDOTHELIUM; METABOLISM; PHYSIOLOGY;

BIOLOGICAL TRANSPORT, ACTIVE; BLOOD-BRAIN BARRIER; HUMANS; MEMBRANE TRANSPORT PROTEINS; PHARMACEUTICAL PREPARATIONS;

EID: 0013117931     PISSN: 03621642     EISSN: None     Source Type: Book Series    
DOI: 10.1146/annurev.pharmtox.43.100901.140204     Document Type: Review

References (157)

1. Ehrlich P. 1885. Das Sauerstoffbedürfnis des Organismus; Eine Farbenanalytische Studie. Berlin: Hirschwald
2. Goldman EE. 1909. Die aussere und innere Sekretion des gesunden und kranken Organismus im Lichte der vitalen Farbung. Beitr. Klin. Chir. 64:192-265
3. Guyton AC. 1981. Textbook of Medical Physiology, p. 358. New York: Saunders
4. Minn A, Ghersi-Egea J-F, Perrin R, Leinigner B, Siest G. 1991. Drug metabolizing enzyme in the brain and cerebral microvessels. Brain Res. Rev. 16:65-82
5. van Bree JBMM, de Boer AG, Danhof M, Ginsel LA, Breimer DD. 1988. Characterization of an in vitro blood-brain barrier: effects of molecular size and lipophilicity on cerebrovascular endothelial transport rates of drugs. J. Pharmacol. Exp. Ther. 247:1233-39
6. Brodie BB, Kurz H, Shanker LS. 1960. The importance of dissociation constant and lipid solubility in influencing the passage of drugs into the central nervous system. J. Pharmacol. Exp. Ther. 130:519-28
7. Palm K, Luthman K, Ungell AL, Strandlund G, Beigi F, et al. 1998. Evaluation of dynamic polar molecular surface area as predictor of drug absorption: comparison with other computational and experimental predictors. J. Med. Chem. 41(27): 5382-92
8. Deleted in proof
9. Reed DJ. 1980. Drug transport into the central nervous system. In Antiepileptic Drugs: Mechanisms of Action, ed. GH Glaser, JK Pentry, DM Woodbury, pp. 199-205. New York: Raven
10. Butt AM, Jones EC, Abbott NJ. 1990. Electrical resistance across the blood-brain barrier in anaesthetized rats: a developmental study. J. Physiol. 429:47-62
11. Janzer RC, Raff MC. 1987. Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 325:253-57
12. Lee G, Dallas S, Hong M, Bendayan R. 2001. Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations. Pharmacol. Rev. 53:569-96
13. Kusuhara H, Sugiyama Y. 2001. Efflux transport systems for drugs at the blood-brain barrier and blood-cerebrospinal fluid barrier. Part 1. Drug Discov. Today 6(3):150-56
14. Kusuhara H, Sugiyama Y. 2001. Efflux transport systems for drugs at the blood-brain barrier and blood-cerebrospinal fluid barrier. Part 2. Drug Discov. Today 6(4):206-12
15. Tamai I, Tsuji A. 2000. Transporter-mediated permeation of drugs across the blood-brain barrier. J. Pharm. Sci. 89:1371-88
16. Moor ACE, de Vries HE, de Boer AG, Breimer DD. 1994. The blood-brain barrier and multiple sclerosis. Biochem. Pharmacol. 47:1717-24
17. Claudio L. 1996. Ultrastructural features of the blood-brain barrier in biopsy tissue from Alzheimer's patients. Acta Neuropathol. 91:6-14
18. Rhodes RH. 1991. Evidence of serum-protein leakage across the blood-brain barrier in the acquired immunodeficiency syndrome. J. Neuropathol. Exp. Neurol. 50:171-83
19. Moses AV, Nelson JA. 1994. HIV infection of human brain capillary endothelial cells: implications for AIDS dementia. Adv. Neuroimmunol. 4:239-47
20. Tunkel A, Scheld WM. 1993. Pathogenesis and pathophysiology of bacterial meningitis. Annu. Rev. Med. 44:103-20
21. Black PH. 1994. Central nervous system-immune systems interactions: psychoneuroendocrinology of stress and its immune consequences. Antimicrob. Agents Chemother. 38(1):1-6
22. de Vries HE, Kuiper J, de Boer AG, van Berkel TJC, Breimer DD. 1997. The blood-brain barrier in neuroinflammatory diseases. Pharmacol. Rev. 49(2):143-55
23. Franke H, Galla H-J, Beuckmann CT. 1999. An improved low-permeability in vitro-model of the blood-brain barrier: transport studies on retinoids, sucrose, haloperidol, caffeine and mannitol. Brain Res. 818:65-71
24. Gaillard PJ, van der Meide PH, de Boer AG, Breimer DD. 2001. Glucocorticoid and type I interferon interactions at the blood-brain barrier: relevance for drug therapies for multiple sclerosis. NeuroReport 1210:2189-93
25. Jancso G, Domiki F, Santha P, Varga J, Fischer J, et al. 1998. Beta-amyloid (1-42) peptide impairs blood-brain function after intracarotid infusion in rats. Neurosci. Lett. 253:139-41
26. Thomas T, Thomas G, McLendon C, Sutton T, Mullan M. 1996. Beta-amyloid-mediated vasoactivity and vascular endothelial damage. Nature 380:168-71
27. Mulder M, Blokland A, van den Berg DJ, Schulten H, Bakker AH, et al. 2001. Apolipoprotein E protects against neuropathology induced by a high-fat diet and maintains the integrity of the blood-brain during aging. Lab. Invest. 81(7):953-60
28. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, et al. 1993. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261:921-23
29. Plump AS, Smisth JD, Hayek T, Aalto-Setala K, Walsh A, et al. 1992. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 71:343-53
30. Gumbleton M, Audus KL. 2001. Progress and limitations in the use of in vitro cell cultures to serve as a permeability screen for the blood-brain barrier. J. Pharm. Sci. 9011:1681-98
31. de Boer AG, Gaillard PJ. 2002. In vitro models of the blood-brain barrier: when to use which? Curr. Med. Chem. Cent. Nerv. Syst. Agents. In press
32. de Lange ECM, de Boer AG, Breimer DD. 1999. Microdialysis for pharmacokinetic analysis of drug transport to the brain. Adv. Drug Deliv. Rev. 36:211-27
33. Pardridge WM. 2001. BBB genomics: new openings for brain drug-targeting. Drug Discov. Today 68:381-83
34. Mellman I. 1996. Endocytosis and molecular sorting. Annu. Rev. Cell Dev. Biol. 12:575-625
35. Gumbleton M, ed. 2001. Caveolae-mediated membrane transport. Adv. Drug Deliv. Rev. 49(3):217-337 (Spec. Issue)
36. Steinman RM, Mellman IS, Muller WA, Cohn ZA. 1983. Endocytosis and the recycling of plasma membrane. J. Cell Biol. 96:1-27
37. Munn AL. 2001. Molecular requirements for the internalisation step of endocytosis: insights from yeast. Biochem. Biophys. Acta 1535:236-57
38. Palade GE. 1953. Fine structure of blood capillaries. J. Appl. Phys. 24:1424-30
39. Couet J, Belanger MM, Roussel E, Drolet M-C. 2001. Cell biology of caveolae and caveolin. Adv. Drug Deliv. Rev. 49:223-35
40. Martin-Belmonte F, Puertollano R, Millan J, Alonso MA. 2000. The MAL proteolipid is necessary for the overall apical delivery of membrane proteins in the polarized epithelial Madin-Darby canine kidney and Fischer rat thyroid cell lines. Mol. Biol. Cell 11:2033-45
41. Anderson RG. 1998. The caveolae membrane system. Annu. Rev. Biochem. 67:199-225
42. Cordon-Cardo CJ, O'Brien JP, Casals D, Rittman-Grauer L, Biedler JL, et al. 1989. Multidrug-resistance gene P-glycoprotein is expressed by endothelial cells at blood-brain barrier sites. Proc. Natl. Acad. Sci. USA 86:695-98
43. Gottesman MM. 1993. How cancer cells evade chemotherapy: Sixteenth Richard and Hindo Rosenthal Foundation Award Lecture. Cancer Res. 53:747-54
44. Zhang Y, Han HY, Elmquist WF, Millen DW. 2000. Expression of various multidrug resistance-associated protein MRP homologues in brain microvessel endothelial cells. Brain Res. 876:148-53
45. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC. 1987. Cellular localization of the multidrug resistance gene product in normal human tissues. Proc. Natl. Acad. Sci. USA 84:7735-38
46. Demeule M, Jodoin J, Gingras D, Beliveau R. 2000. P-glycoprotein is localized in caveolae in resistant cells and in brain capillaries. FEBS Lett. 466:219-24
47. Schinkel AH, Wagenaar E, van Deemter L, Mol CAAM, Borst P. 1995. Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin. Am. J. Clin. Invest. 96(4): 1698-705
48. Smit JJ, Schinkel AH, Oude-Elferink RP, Groen AK, Wagenaar E, et al. 1993. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell 75(3):451-62
49. Gottesman MM, Pastan I. 1993. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu. Rev. Biochem. 62:385-427
50. Higgins CF, Gottesman MM. 1992. Is the multidrug transpoter a flippase? Trends Biochem. Sci. 17:18-21
51. Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesmann MM. 1999. Biochemical, cellular and pharmacological aspects of the multidrug transporter. Annu. Rev. Pharmacol. Toxicol. 39:361-98
52. Borst P, Schinkel AH. 1996. What have we learnt thus far from mice with disrupted P-glycoprotein genes. Eur. J. Cancer 32(A6):985-90
53. Croop JM, Raymond M, Haber D, Devault A, Arceci RJ. 1989. The three mouse multidrug resistance mdr genes are expressed in a tissue-specific manner in normal mouse tissues. Mol. Cell. Biol. 9:1246-50
54. MacFarland A, Abramovich DR, Ewen SW, Pearsson CK. 1994. Stage-specific distribution of P-glycoprotein in first-trimester and full-term human placenta. Histochem. J. 26:417-23
55. Karssen AM, Meijer OC, van der Sandt ICJ, Lucassen PJ, de Lange ECM, et al. 2001. Multidrug resistance P-glycoprotein hampers the access of cortisol but not of corticosterone to mouse and human brain. Endocrinology 142(6):2686-94
56. Meijer OC, de Lange ECM, Breimer DD, de Boer AG, Workel JO, de Kloet ER. 1998. Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdr1A P-glycoprotein knockout mice. Endocrinology 139(4):1789-93
57. Idriss HT, Hannun YA, Boulpaep E, Basavappa S. 2000. Regulation of volume-activated chloride channels by P-glycoprotein: phosphorylation has the final say. J. Physiol. 524(3):629-36
58. Zhang L, Sachs CW, Fu HW, Fine RL, Casey PJ. 1995. Characterization of prenylcysteines that interact with P-glycoprotein and inhibit drug transport in tumor cells. J. Biol. Chem. 270:22859-65
59. Field FJ, Born E, Chen H, Murthy S, Mathur SN. 1995. Esterification of plasma membrane cholesterol and triacylglycerol-rich lipoprotein secretion in CaCo-2 cells: a possible role of P-glycoprotein. J. Lipid. Res. 36:1533-43
60. Wang EJ, Casciano CN, Clement RP, Johnson WW. 2000. Cholesterol interaction with the daunorubicin binding site of P-glycoprotein. Biochem. Biophys. Res. Commun. 276(3):909-16
61. Lam FC, Liu R, Lu P, Shapiro AB, Renoir JM, et al. 2001. Beta-amyloid efflux mediated by P-glycoprotein. J. Neurochem. 76:1121-28
62. Schinkel AH, Mayer U, Wagenaar E, Mol CAAM, van Deemter L. 1997. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J. Clin. Invest. 97(11):2517-24
63. Ayrton A, Morgan P. 2001. Role of transport proteins in drug absorption, distribution and excretion. Xenobiotica 31(8/9):469-97
64. Callaghan R, Riordan JR. 1993. Synthetic and natural opiates interact with P-glycoprotein in multidrug-resistant cells. J. Biol. Chem. 268:16059-64
65. Zong J, Pollack GM. 2000. Morphine antinociception is enhanced in mdr1a gene-deficient mice. Pharm. Res. 17(6): 749-53
66. Letrent SP, Pollack GM, Brouwer KR, Brouwer KLR. 1999. Effects of a potent and specific P-glycoprotein inhibitor on the blood-brain barrier distribution and antinociceptive effect of morphin in the rat. Drug Metab. Dispos. 27(7):827-34
67. Potschka H, Loscher W. 2001. In vivo evidence for P-glycoprotein-mediated transport of phenytoin at the blood-brain barrier of rats. Epilepsia 42(10):1231-40
68. Cox DS, Scott KR, Gao H, Jaje S, Eddington ND. 2001. Influence of multidrug resistance MDR proteins at the blood-brain barrier on the transport and brain distribution of enaminone anticonvulsants. J. Pharm. Sci. 90(10):1540-52
69. Gaillard PJ, Voorwinden LH, Nielsen JL, Ivanov A, Atsumi R, et al. 2001. Establishment and functional characterization of an in vitro model of the blood-brain barrier, comprising a co-culture of brain capillary endothelial cells and astrocytes. Eur. J. Pharm. Sci. 12:215-22
70. van der Sandt ICJ, Gaillard PJ, Voorwinden LH, de Boer AG, Breimer DD. 2001. P-glycoprotein inhibition leads to enhanced disruptive effects by anti-microtubule cytostatics at the in vitro blood-brain barrier. Pharm. Res. 18(5): 587-92
71. Fenart L, Buee-Scherrer V, Descamps L, Duhem C, Poullain MG, et al. 1998. Inhibition of P-glycoprotein: rapid assessment of its implication in blood-brain barrier integrity and drug transport to the brain by an in vitro model of the blood-brain barrier. Pharm. Res. 15(7):993-1000
72. Hebert MF, Lam AY. 1999. Diltiazem increases tacrolimus concentrations. Ann. Pharmacother. 33:680-82
73. 1A receptor antagonist flesinoxan via P-glycoprotein at the blood-brain barrier. Eur. J. Pharm. Sci. 14:81-86
74. Levy RM, Bredesen DE, Rosenblum ML. 1985. Neurological manifestations of the acquired immunodeficiency syndrome (AIDS): experience at UCSF and review of the literature. J. Neurosurg. 101(2):289-94
75. Tardieu M. 1999. HIV-1 related central nervous system diseases. Curr. Opin. Neurol. 12(4):377-81
76. Glynn SL, Yazdanian M. 1998. In vitro blood-brain barrier permeability of nevirapine compared to other HIV antiretroviral agents. J. Pharm. Sci. 87(3):306-10
77. van der Sandt ICJ, Vos CMP, Nabulsi LM, Blom-Roosemalen MCM, Voorwinden LH, et al. 2001. Assessment of active transport of HIV protease inhibitiors in various cell lines and the in vitro blood-brain barrier. AIDS 15(4):483-91
78. Huisman MT, Smit JW, Wiltshire HR, Hoetelmans RM, Beijnen JH, Schinkel AH. 2001. P-glycoprotein limits oral availabilty, brain and fetal penetration of saquinavir even with high doses of ritonavir. Mol. Pharmacol. 59(4):806-13
79. Jonker JW, Wagenaar E, Van Deemter L, Gottschlich R, Bender HM, et al. 1999. Role of blood-brain barrier P-glycoprotein in limiting brain accumulation and sedative side-effects of asimado-line, a peripherally acting analgaesic drug. Br. J. Pharmacol. 127:43-50
80. Chishty M, Reichel A, Siva J, Abbott NJ, Begley DJ. 2001. Affinity for the P-glycoprotein efflux pump at the blood-brain barrier may explain the lack of CNS side-effects of modern antihistamines. J. Drug Target 93:223-28
81. Matheny CJ, Lamb MW, Brower KR, Pollack GM. 2001. Pharmacokinetic and pharmacodynamic implications of P-glycoprotein modulation. Pharmacotherapy 21(7):778-96
82. Gruol DJ, Zee MC, Trotter J, Bourgeois S. 1994. Reversal of multidrug resistance by RU 486. Cancer Res. 54:3088-91
83. Beck WT, Cirtain MC. 1982. Continued expression of vinca alkaloid resistance by CCRF-CEM cells after treatment with tunicamycin or pronase. Cancer Res. 42:184-89
84. Chambers TC, Zheng B, Kuo JF. 1992. Regulation by phorbol ester and protein kinase C inhibitors, and by a protein phosphatase inhibitor okadaic acid, of Pgp-phosphorylation and relationship to drug accumulation in multidrug-resistant human KB cells. Mol. Pharmacol. 416:1008-15
85. Bates SE, Lee JS, Bickstein B, Spolyar M, Fojo AT. 1993. Differential modulation of P-glycoprotein transport by protein kinase inhibition. Biochemistry 32:9156-64
86. Fine RL, Patel J, Chabner BA. 1988. Phorbol esters induce multidrug resistance in human breast cancer cells. Proc. Natl. Acad. Sci. USA 85:582-86
87. Hoffmann J. 2001. Modulation of protein kinase C in antitumor treatment. Rev. Physiol. Biochem. Pharmacol. 142:1-96
88. Felix RA, Barrand MA. 2002. P-glycoprotein expression in rat brain endothelial cells: evidence for regulation by transient exidative stress. J. Neurochem. 80(1):64-72
89. Kis B, Deli MA, Kobayashi H, Abraham CS, Yanagita T, et al. 2001. Adrenomedullin regulates blood-brain barrier functions in vitro. NeuroReport 12(18):4139-42
90. Matsuo H, Wakasugi M, Takanaga H, Ohtani H, Noito M, et al. 2001. Possibility of the reversal of multidrug resistance and the avoidance of side effects by liposomes modified with MRK-16, a monoclonal antibody to P-glycoprotein. J. Control Release 77:77-86
91. Hopper E, Belinsky MG, Zeng H, Tosoline A, Testa JR, Kruh GD. 2001. Analysis of the structure and expression pattern of MRP7 ABCC10, a new member of the MRP subfamily. Cancer Lett. 162(2):181-91
92. Borst P, Evers R, Kool M, Wijnholds J. 1999. The multidrug resistance protein family. Biochem. Biophys. Acta 1461:347-57
93. Borst P, Evers R, Kool M, Wijnholds J. 2000. A family of drug transporters: the multidrug resistance-associated proteins. J. Natl. Cancer Inst. 92:1295-302
94. Gao M, Loe DW, Grant CE, Cole SPC, Deeley RG. 1996. Reconstitution of ATP-dependent leukotriene C4 transport by co-expression of both half-molecules of human multidrug resistance protein in insect cells. J. Biol. Chem. 271:27782-87
95. Bakos E, Evers R, Szakacs G, Tusnady GE, Welker E, et al. 1998. Functional multidrug resistance protein MRP1 lacking the N-terminal transmembrane domain. J. Biol. Chem. 273:32167-75
96. Klein I, Sarkadi B, Varadi A. 1999. An inventory of the human ABC proteins. Biochim. Biophy. Acta 1461:237-62
97. Sekine T, Cha SH, Endou H. 2000. The multispecific organic anion transporter OAT family. Pflügers Arch. 89:337-44
98. Gao G, Hagenbuch B, Kullak-Ublick GA, Benke D, Aguzzi A, Meier PJ. 2000. Organic anion-transporting polypeptides mediate transport of opioid peptides across blood-brain barrier. J. Pharmacol. Exp. Ther. 294(1):73-79
99. Asaba H, Hosoya K, Takanaga H, Ohtsuki S, Tamura E, et al. 2000. Blood-brain barrier is involved in the efflux transport of a neuroactive steroid, dehydroepiandrosterone sulphate, via organic anion transporting polypeptide 2. J. Neurochem. 75:1907-16
100. Kakyo M, Sakagami H, Nishio T, Nakai D, et al. 1999. Immunohistochemical distribution and functional characterization of an organic anion transporting polypeptide 2 oatp2. FEBS Lett. 445:343-46
101. Sugiyama D, Kusuhara H, Shitara Y, Abe T, Meier PJ, et al. 2001. Characterization of the efflux transport of 17-beta-estradiol-D-17-beta-glucoronide from the brain across the blood-brain barrier. J. Pharmacol. Exp. Ther. 298(1):316-22
102. Fox IH, Kelley WN. 1978. The role of adenosine and 2′ -deoxyadenosine in mammalian cells. Annu. Rev. Biochem. 47:655-86
103. Daval JL, Nehlig A, Nicolas F. 1991. Physiological and pharmacological properties of adenosine: therapeutic implications. Life Sci. 49:1435-53
104. Cass CE, Young JD, Baldwin SA. 1998. Recent advances in the molecular biology of nucleoside transporters of mammalian cells. Biochem. Cell. Biol. 76:761-70
105. Thomas SA, Segal MB. 1997. Saturation kinetics, specificity and NBMPR sensitivity of thymidine entry into the central nervous system. Brain Res. 760:59-67
106. Anderson CM, Xiong W, Geiger JD, Young JD, Cass CE, et al. 1999. Distribution of equilibrative, nitrobenzylthioinosine-sensitive nucleoside transporters ENT1 in brain. J. Neurochem. 73:876-73
107. Anderson CM, Baldwin SA, Young JD, Cass CE, Parkinson FE. 1999. Distribution of mRNA encoding a nitrobenzylthioinosine-insensitive nucleoside transporter ENT2 in rat brain. Brain Res. Mol. Brain Res. 70:293-97
108. Terasaki T, Pardridge WM. 1988. Restricted transport of 3′-azido-3′-deoxythymidine and dideoxynucleosides through the blood-brain barrier. J. Infect. Dis. 158:630-32
109. + nucleoside transporter CNT2 cloned from rat blood-brain barrier. J. Pharmacol. Exp. Ther. 299(2):735-40
110. Kanai Y, Segawa H, Miyamoto K, Uchino H, Takeda E, Endou H. 1998. Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen CD98. J. Biol. Chem. 273:23629-32
111. Boado RJ, Li JY, Nagaya M, Zhang C, Pardridge WM. 1999. Selective expression of the large neutral amino acid transporter at the blood-brain barrier. Proc. Natl. Acad. Sci. USA 96(21):12079-84
112. Pardridge WM. 1983. Brain metabolism: a perspective from the blood-brain barrier. Physiol. Rev. 63:1481-535
113. Pardridge WM. 1998. Blood-brain barrier carrier-mediated transport and brain metabolism of amino acids. Neurochem. Res. 23:635-44
114. Pardridge WM. 1986. Blood-brain barrier transport of nutrients. Nutr. Rev. 44(Suppl.):15-25
115. +-independent neutral amino acid transporter with broad substrate selectivity. J. Biol. Chem. 274:19745-51
116. Killian DM, Chikhale PJ. 2001. Predominant functional activity of the large, neutral amino acid transporter LAT1 isoform at the cerebrovasculature. Neurosci. Lett. 306:1-4
117. Huang SC, Stour DB, Yee RE, Satyamurthy N, Barrio JR. 1998. Distribution volume of radiolabeled large neutral amino acids in brain tissues. J. Cereb. Blood Flow Metab. 18(12):1288-93
118. Shulkin BL, Betz AL, Koeppe RA, Agranoff BW. 1995. Inhibition of neutral amino acid transport across the human blood-brain barrier by phenylalanine. J. Neurochem. 64(3):1252-57
119. Cornford EM, Young D, Paxton JW, Finlay GJ, Wilson WR, Pardridge WM. 1992. Melphalan penetration of the blood-brain barrier via the neutral amino acid transporter in tumor-bearing brain. Cancer Res. 52(1):138-43
120. Pietz J, Kreis R, Rupp A, Mayatepek E, Rating D, et al. 1999. Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. J. Clin. Invest. 1038:1169-78
121. Hokari M, Wu HQ, Schwarcz R, Smith QR. 1996. Facilitated brain uptake of 4-chlorohynurenine and conversion to 7-chlorokynurenic acid. NeuroReport 8(1): 15-18
122. Ponka P, Lok CN. 1999. The transferrin receptor: role in health and disease. Int. J. Biochem. 31(10):1111-37
123. Schneider C, Owen MJ, Banville D, Williams JG. 1984. Primary structure of human transferrin receptor deduced from the mRNA sequence. Nature 311:675-78
124. Jing S, Trowbridge IS. 1987. Identification of the intermolecular disulfide bonds of the human transferrin receptor and its lipid-attachment site. EMBO J. 6:327-31
125. Jefferies WA, Brandon, MR, Hunt, SV, Williams AF, Gatter, KC, Mason DY. 1984. Transferrin receptor on endothelium of brain capillaries. Nature 312:162-63
126. Kawabata H, Germain RS, Vuong PT, Nakamaki T, Said JW, Koeffler HP. 2000. Transferrin receptor 2-alpha supports cell growth both in iron-chelated cultured cells and in vivo. J. Biol. Chem. 275:16618-25
127. Collawn JF, Stangel M, Kuhn L, Esekogwu V, Jing S, et al. 1990. Transferrin receptor internalization sequence YXRF implicates a tight turn as the structural recognition motif for endocytosis. Cell 63:1061-72
128. Snider MD, Rogers OC. 1986. Membrane traffic in animal cells: cellular glycoproteins return to the site of Golgi mannosidase. J. Cell Biol. 103:265-75
129. van Gelder W, Huijskes-Heins MIE, van Dijk JP, Cleton-Soeteman MI, van Eijk HG. 1995. Quantification of different transferrin receptor pools in primary cultures of porcine blood-brain barrier endothelial cells. J. Neurochem. 64:2708-15
130. Taylor EM, Morgan EH. 1991. Role of transferrin in iron uptake by the brain: a comparative study. J. Comp. Physiol. B 161:521-24
131. Malomi W, Testa U, Rainaldi G, Tritarelli E, Peschle C. 1998. Oxidative stress leads to a rapid alteration of transferrin receptor intravesicular trafficking. Exp. Cell. Res. 241(1):102-16
132. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Basava DA, et al. 1996. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat. Genet. 13:399-408
133. Fleming MD, Trenor CC III, Su MA, Foernzler D, Beier DR, et al. 1997. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat. Genet. 16:383-86
134. Roy CN, Penny DM, Feder JN, Enns CA. 1999. The hereditary hemochomatosis protein, HFE, specifically regulates transferrin-mediated iron uptake in HeLa cells. J. Biol. Chim. 274:9022-28
135. Qian ZM, Shen X. 2001. Brain iron transport and neurodegeneration. Trends Mol. Med. 7:103-8
136. Raub TJ, Newton CR. 1991. Recycling kinetics and transcytosis of transferrin in primary cultures of bovine brain microvessel endothelial cells. J. Cell. Physiol. 149:141-51
137. Deleted in proof
138. Descamps L, Dehouck M-P, Torpier G, Cecchelli R. 1996. Receptor-mediated transcytosis of transferrin through blood-brain barrier endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 39:1149-58
139. Zhang Y, Pardridge WM. 2001. Neuroprotection in transient focal brain ischemia after delayed intravenous administration of brain-derived neurotrophic factor conjugated to a blood-brain barrier drug targeting system. Stroke 32(6):1378-84
140. Shi N, Pardridge WM. 2000. Noninvasive gene targeting to the brain. Proc. Natl. Acad. Sci. USA 97(13):7567-72
141. Shi N, Boado RJ, Pardridge WM. 2001. Receptor-mediated gene targeting to tissues in vivo following intravenous administration of pegylated immunoliposomes. Pharm. Res. 18(8):1091-95
142. Jefferies WA, Food MR, Gabathuler R, Rothenberger S, Yamada T, et al. 1996. Reactive microglia specifically associated with amyloid plaques in Alzheimer's disease brain tissue express melanotransferrin. Brain Res. 712:122-26
143. de Vries HE, Kuiper J, de Boer AG, van Berkel TJC, Breimer DD. 1993. Characterization of the scavenger receptor on bovine cerebral endothelial cells in vitro. J. Neurochem. 61:1813-21
144. Goti D, Hrzenjak A, Levak-Frank S, Frank S, van der Westhyzen DR, et al. 2001. Scavenger receptor class B, type I is expressed in porcine brain capillary endothelial cells and contributes to selective uptake of HDL-associated vitamin E. J. Neurochem. 76(2):498-508
145. Krieger M. 2001. Scavenger receptor class B type I is a multi-ligand HDL receptor that influences diverse physiologic systems. J. Clin. Invest. 108(6):793-97
146. Calvo D, Vega MA. 1993. Identification, primary structure, and distribution of CLA-1, a novel member of the CD36/LIMPII gene family. J. Biol. Chem. 268:18929-35
147. Graf CA, Connell PM, van der Westhuyzen DR, Smart EJ. 1999. SR-B1 promotes the selective uptake of HDL choesterol esters into caveolae. J. Biol. Chem. 274:12043-48
148. Silver DL, Tall AR. 2001. The cellular biology of scavenger receptor class B type I. Curr. Opin. Lipidol. 12:497-504
149. Silver DL, Nan W, Xiao X, Tall AR. 2001. HDL particle uptake mediated by SR-BI results in selective sorting of HDL cholesterol from protein and polarized cholesterol secretion. J. Biol. Chem. 276:25287-93
150. Nakamura M, Davila-Zavala P, Tokuda H, Takakura Y, Hashida M. 1998. Uptake and gene expression of naked plasmid DNA in cultured brain microvessel endothelial. Biochem. Biophys. Res. Commun. 245(1):35-39
151. Mockel B, Zinke H, Flach R, Weiss B, Weilar-Guttler H, Gassen HG. 1994. Expression of apolipoprotein A-I in porcine brain endothelium in vitro. J. Neurochem. 62(2):788-98
152. Koudinov A, Matsubara E, Frangione B, Ghiso J. 1994. The soluble form of Alzheimer's amyloid beta protein is complexed to high density lipoprotein 3 and very high density lipoprotein in normal human plasma. Biochem. Biophys. Res. Commun. 205(2):1164-71
153. Mackic JB, Stins M, McComb JG, Calero M, Ghiso J, et al. 1998. Human blood-brain barrier receptors for Alzheimer's amyloid-beta 1-40. Asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell monolayer. J. Clin. Invest. 1024:734-43
154. Breimer DD, Danhof M. 1997. Relevance of the application of pharmacokinetic-pharmacodynamic modelling concepts in drug development, the "wooden shoe" paradigm. Clin. Pharmacokinet. 32:259-67
155. Janeway CA. 1989. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harbor Symp. Quant. Biol. 54:1-13
156. Krieger M. 1997. The other side of scavenger receptors: pattern recognition for host defense. Curr. Opin. Lipidol. 8:275-80
157. de Boer B, Gaillard P, van der Sandt I. 2001. De bloed-hersenbarriere en het transport van geneesmiddelen naar de hersenen. Neuropraxis 5:142-49