Determinants of passive drug entry into the central nervous system

Cellular and Molecular Neurobiology

Volumn 20, Issue 2, 2000, Pages 231-253

  Habgood, M D ^a   Begley, D J ^b   Abbott, N J ^b  

^a UNIVERSITY OF TASMANIA   (Australia)

^b KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

Blood brain barrier; Lipid solubility; Passive permeability

Indexed keywords

DEFERIPRONE;

BLOOD BRAIN BARRIER; CENTRAL NERVOUS SYSTEM; COMPETITIVE INHIBITION; DRUG ACCUMULATION; DRUG DIFFUSION; DRUG PENETRATION; DRUG TRANSPORT; HYDROGEN BOND; HYDROXYLATION; LIPID SOLUBILITY; METHYLATION; MOLECULAR INTERACTION; MOLECULAR SIZE; POLARIZATION; PRIORITY JOURNAL; REVIEW; SOLVATION;

ANIMALS; BIOLOGICAL TRANSPORT; BLOOD-BRAIN BARRIER; CENTRAL NERVOUS SYSTEM; CENTRAL NERVOUS SYSTEM DISEASES; DIFFUSION; HUMANS; PHARMACEUTICAL PREPARATIONS;

EID: 0033981738     PISSN: 02724340     EISSN: None     Source Type: Journal    
DOI: 10.1023/A:1007001923498     Document Type: Review

References (121)

1. Abbott, N. J. (2000). Inflammatory mediators and modulation of blood-brain barrier permeability. Cell. Mol. Neurobiol. 20:131-147.
2. Abraham, M. H. (1993). Scales of solute hydrogen bonding: Their construction and application to physicochemical and biochemical processes. Chem. Soc. Rev. 22:73-83.
3. Abraham, M. H., and Chadha, H. S. (1996). Applications of solvation equation to drug transport properties. In Pliska, V., Testa, B., and van de Waterbeemd, H. (eds.), Lipophilicity in Drug Action and Toxicity, VCH, Weinheim, Germany, pp. 311-337.
4. Abraham, M. H., and McGowan, J. C. (1987). The use of characteristic volumes to measure cavity terms in reversed phase liquid chromatography. Chromatographia 23:243-246.
5. Abraham, M. H., Whiting, G. S., Doherty, R. M., and Shuely, W. J. (1990). Hydrogen bonding part 13. A new method for characterisation of GLC stationary phases - The Laffort dataset. J. Chem. Soc. Perkin Trans. 2:1451-1460.
6. Abraham, M. H., Whiting, G. S., Doherty, R. M., and Shuely, W. J. (1991). Hydrogen bonding. XVI. A new solute solvation parameter, pi2(H), from gas Chromatographic data. J. Chromatogr. 587:213-228.
7. Abraham, M. H., Chadha, H. S., Whiting, G. S., and Mitchell, R. C. (1994a). Hydrogen bonding part 32: An analysis of water-octanol and water-alkane partitioning and the Δlog P parameter of Seiler. J. Pharm. Sci. 83:1085-1100.
8. Abraham, M. H., Chadha, H. S., and Mitchell, R. C. (1994b). Hydrogen bonding part 33: The factors that influence the distribution of solutes between blood and brain. J. Pharm. Sci. 83:1257-1268.
9. Abraham, M. H., Chadha, H. S., and Mitchell, R. C. (1995). Hydrogen bonding part 37: The factors that influence skin penetration of solutes. J. Pharm. Pharmacol. 47:8-16.
10. Anderson, B. D. (1996). Prodrugs for improved CNS delivery. Adv. Drug Deliv. Rev. 19:171-202.
11. Arendt, R. M., Greenblatt, D. J., Liebisch, D. C., Luu, M. D., and Paul, S. M. (1987). Determinants of benzodiazepine brain uptake: Lipophilicity versus binding affinity. Psychopharmacology 93:72-76.
12. Bartus, R. T., Elliot, P. J., Hayward, N. J., Dean, R. L., McEwen, E., and Fisher, S. K. (1996). Bradykinin permeation of the blood-brain barrier: Evidence for a sensitive auto-regulated, receptor mediated system. Immunopharmacology 33:270-278.
13. Becker, H., and Quadbeck, G. (1952a). Tierexperimentelle Untersuchungen u. d. Funktionweise der Blut Hirnschranke. Z. Naturforsch. 7B:493-497.
14. Becker, H., and Quadbeck, G. (1952b). Untersuchungen uber Funktionsstorungen der Blut Hirnschranke bei Sauerstoffmangel und Kohlenoxydvergiftung mit dem neuen Schrankenindikator Astroviolett FF. Z. Naturforsch. 7B:498-500.
15. Begley, D. J., Chen, Z. D., Rollinson, C., and Abbott, N. J. (1994). Activity of P-glycoprotein (multidrug resistance protein) in cultured immortalised rat brain microvascular endothelial cells (RBE4). J. Physiol. 480:9P.
16. Bradbury, M. W. B. (1979). The Concept of a Blood-Brain Barrier, John Wiley and Sons, New York.
17. Brightman, M. W. (1977). Morphology of the blood-brain barrier interfaces. Exp. Eye Res. 25:1-25.
18. Brightman, M. W. (1992). Ultrastructure of brain endothelium. Hand. Exp. Pharm. 103:1-22.
19. Brightman, M. W., and Reese, T. S. (1969). Junctions between intimately apposed cell membranes in the vertebrate brain. J. Cell Biol. 40:648-677.
20. Broadwell, R. D., Baker-Cairns, B. J., Friden, P. M., Oliver, C., and Villegas, J. C. (1996). Transcytosis of protein through the mammalian cerebral epithelium and endothelium. III. Receptor-mediated transcytosis through the blood-brain barrier of blood-borne transferrin and antibody against the transferrin receptor. Exp. Neurol. 142:47-65.
21. Bundgaard, H. (1987). Design of bioreductive derivatives and the utility of the double prodrug concept. In Roche, E. B. (ed.), Bioreversible Carriers in Prodrug Design, Theory and Application, Pergamon, New York, pp. 13-94.
22. Butt, A. M., Jones H. C., and Abbott, N. J. (1990). Electrical resistance across the blood-brain barrier in anaesthetized rats: A developmental study. J. Physiol. 429:47-62.
23. Chen, A. Y., Yu, C., Potmesil, M., Wall, M. E., Wani, M. C., and Liu, L. F. (1991). Camptothecin overcomes mdr1-mediated resistance in human kb carcinoma-cells. Cancer Res. 51:6039-6044.
24. Cordon-Cardo, C., O'Brien, J. P., Casals, D., Rittman-Grauer, L., Biedler, J. L., Melamed, M. R., and Bertino, J. R. (1989). Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc. Natl. Acad. Sci. USA 86:695-698.
25. Cornford, E. M., Braun, L. D., Oldendorf, W. H., and Hill, M. A. (1982). Comparison of lipid-mediated blood-brain barrier penetrability in neonates and adults. Am. J. Physiol. 243:C161-C168.
26. Crone, C., and Christensen, O. (1981). Electrical resistance of a capillary endothelium. J. Gen. Physiol. 77:349-371.
27. Crone, C., and Olesen, S. P. (1981). The electrical-resistance of brain capillary endothelium. J. Physiol. 316:53-54.
28. Crone, C., and Olesen, S. P. (1982). Electrical-resistance of brain micro-vascular endothelium. Brain Res. 241:49-55.
29. Croop, J. M., Raymond, M., Haber, D., Devault, A., Arceci, R. J., Gros, P., and Housman, D. E. (1989). The 3 mouse multidrug resistance (mdr) genes are expressed in a tissue-specific manner in normal mouse-tissues. Mol. Cell. Biol. 9:1346-1350.
30. Davson, H., and Danielli, J. F. (1943). The Permeability of Natural Membranes, Cambridge University Press, Cambridge.
31. Davson, H., and Segal, M. B. (1996). Physiology of the CSF and Blood-Brain Barriers, CRC Press, Boca Raton, FL.
32. Dobbin, P. S., Hider, R. C., Hall, A. D., Taylor, P. D., Sarpong, P., Porter J. B., Xiao, G., and van der Helm, D. (1993). Synthesis, physicochemical properties, and biological evaluation of N-substituted 2-alkyl-3-hydroxy-4(1H)-pyridinones: Orally active iron chelators with clinical potential. J. Med. Chem. 36:2448-2458.
33. Drion, N., Lemaire, M., Lefauconnier, J. M., and Scherrmann, J. M. (1996). Role of P-glycoprotein in the blood-brain transport of colchicine and vinblastine. J. Neurochem. 67:1688-1693.
34. During, M. J., Freese, A., Sabel, B. A., Saltzman, W. M., Deutch, A., Roth, R. H., and Langer, R. (1989). Controlled release of dopamine from a polymeric brain implant: In vivo characterization. Ann. Neurol. 25:351-356.
35. Einstein, A. (1905). Uber die von der molekularkinetischen theorie der Earme geforderte bewegung von in ruhenden flussigkeiten suspendierten teilchen. Ann. Phys. 17:549-560.
36. Elliot, P. J., Hayward, N. J., Dean, R. L., Blunt, D. G., and Bartus, R. T. (1996). Intravenous RMP-7 selectively increase uptake of carboplatin into rat brain tumors. Cancer Res. 56:3998-4005.
37. Endicott, J. A., and Ling, V. (1989). The biochemistry of P-glycoprotein mediated multidrug resistance. Annu. Rev. Biochem. 58:137-171.
38. Engler, C. B., Sander, B., Larsen, M., Koefoed, P., Parving, H. H., and Lundandersen, H. (1994). Probenecid inhibition of the outward transport of fluorescein across the human blood retina barrier. Acta Ophthalmol. 72:663-667.
39. Fang, Z., Ionescu, P., Chortkoff, B. S, Kandel, L., Sonner, J., Laster, M. J., and Eger, E. I., 2nd (1997). Anesthetic potencies of n-alkanols: Results of additivity and solubility studies suggest a mechanism of action similar to that for conventional inhaled anesthetics. Anesth. Analg. 84:1042.
40. Felgenhauer, K. (1974). Protein size and cerebrospinal fluid. Klin. Wochenschrift. 52:1158-1164.
41. Fenstermacher, J. D., and Rapoport, S. I. (1984). Blood-brain barrier. In Renkin, E. M., and Michell, C. C. (eds.), Handbook of Physiology, the Cerebrovascular System, Vol. IV, Part 2, American Physiological Society, Bethesda, MD, pp. 969-1000.
42. 14C-sucrose into brain, cerebrospinal fluid, and skeletal muscle of developing rats. Exp. Brain Res. 7:181-194.
43. Fischer, E., Spatz, H., Heller, B., and Reggiani, H. (1972). Phenethylamine content of human urine and rat brain, its alterations in pathological conditions and after drug administration. Experientia 28:307-308.
44. Friden, P. M., Olson, T. S., Obar, R., Walus, L. R., and Putney, S. D. (1996). Characterization, receptor mapping and blood-brain barrier transcytosis of antibodies to the human transferrin receptor. J. Pharmacol. Exp. Ther. 278:1491-1498.
45. Fung, L. K., Ewend, M. G., Sills, A., Sipos, E. P., Thompson, R., Watts, M., Colvin, O. M., Brem, H., and Saltzman, W. M. (1998). Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxy-cyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain. Cancer Res. 58:672-684.
46. Gaveriaux, C., Boesch, D., Boelsterli, J. J., Bollinger, P., Eberle, M. K., Hiestand, P., Payne, T., Traber, R., Wenger, R., and Loor, F. (1989). Overcoming multidrug resistance in Chinese hamster ovary cells in vitro by cyclosporin A (Sandimmune) and non-immunosuppressive derivatives. Br. J. Cancer 60:867-871.
47. Golden, P. L., and Pardridge, W. M. (2000). Brain microvascular P-glycoprotein and a revised model of multidrug resistance in brain. Cell. Molecul. Neurobiol. 20:165-182.
48. Gollapudi, S., Kim, C. H., Tran, B. N., Sangha, S., and Gupta, S. (1997). Probenecid reverses multidrug resistance in multidrug resistance-associated protein overexpressing HL60/AR and H69/AR cells but not in P-glycoprotein overexpressing HL60/Tax and P388/ADR cells. Cancer Chemother. Pharmacol. 40:150-158.
49. Gottesman, M. M., and Pastan, I. (1993). Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu. Rev. Biochem. 62:385-427.
50. Gratton, J. A., Abraham, M. H., Bradbury, M. W., and Chadha, H. S. (1997). Molecular factors influencing drug transfer across the blood-brain barrier. J. Pharm. Pharmacol. 49:1211-1216.
51. Greene, D. L., Hau, V. S., Abbruscato, T. J., Bartosz, H., Misicka, A., Lipkowski, A. W., Hom, S., Gillespie, T. J., Hruby, V. J., and Davis, T. P. (1996). Enkephalin analog prodrugs: Assessment of in vitro conversion, enzyme cleavage characterization and blood-brain barrier permeability. J. Pharmacol. Exp. Ther. 277:1366-1375.
52. Greenwood, J. (1992). Experimental manipulation of the blood-brain and blood-retinal barriers. Hand. Exp. Pharmacol. 103:461-486.
53. Greig, N. H. (1989). Drug delivery to the brain by blood-brain barrier circumvention and drug modification. In Neuwelt E. A. (ed.), Implications of the Blood-Brain Barrier and Its Modification, Vol. 1, Basic Science Studies, Plenum, New York, pp. 179-185.
54. Greig, N. H. (1992). Drug entry into the brain and its pharmacological manipulation. In Bradbury, M. W. B. (ed.), Physiology and Pharmacology of the Blood-Brain Barrier; Handbook of Experimental Pharmacology, Vol. 103, Springer-Verlag, Berlin, pp. 487-523.
55. Greig, N. H., Sweeney, D. J., and Rapoport, S. I. (1987). Melphalan concentration dependent plasma protein binding in healthy humans and rats. Eur. J. Clin. Pharmacol. 32:179-185.
56. Greig, N. H., Sweeney, D. J., and Rapoport, S. I. (1988). Comparative brain and plasma pharmacokinetics and anticancer activities of chlorambucil and melphalan in the rat. Cancer Chemother. Pharmacol. 21:1-8.
57. Greig, N. H., Daley, E. M., Sweeny, D. J., and Rapoport, S. I. (1990). Pharmacokinetics of chlorambuciltertiary butyl ester, a lipophilic chlorambucil derivative that achieves and maintains high concentrations in brain. Cancer Chemother. Pharmacol. 25:311-319.
58. Habgood, M. D., Knott, G. W., Dziegielewska, K. M., and Saunders, N. R. (1993). The nature of the decrease in blood-cerebrospinal fluid barrier exchange during postnatal brain development in the rat. J. Physiol. 468:73-83.
59. Habgood, M. D., ZuDong, L., Dehkordi, L. D., Nazarian, J., Abraham, M., Hider, R. C., and Abbott, N. J. (1997). Chemical structure of drugs and blood-brain barrier permeability. J. Physiol. 505:49P.
60. Hansch, C., and Leo, A. (1979). Substituent Constants for Correlation Analysis in Chemistry and Biology, John Wiley and Sons, New York.
61. Hansch, C., Bjorkroth, J. P., and Leo, A. (1987). Hydrophobicity and central nervous system agents: On the principle of minimal hydrophobicity in drug design. J. Pharm. Sci. 76:663-687.
62. Harbaugh, R. E., Saunders, R. L., and Reeder, R. (1988). Use of implantable pumps for central nervous system drug infusions to treat neurological disease. Neurosurgery 23:693-700.
63. Hardebo, J. E., and Nilsson, B. (1981). Opening of the blood-brain barrier by acute elevation of intracarotid pressure. Acta Physiol Scand. 111:43-49.
64. Hayafil F., Vergely C., Du Vignaud P., and Grand-Perret T. (1993). In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative. Cancer Res. 53:4595-4602.
65. Healy, D. P., and Orlowski, M. (1992). Immunocytochemical localization of endopeptidase 24.15 in rat brain. Brain Res. 571:121-128.
66. Higgins, C. F., and Gottesman, M. M. (1992). Is the multidrug transporter a flippase. TIBS. 17:18-21.
67. Hughes, C. S., Vaden, S. L., Manaugh, C. A., Price, G. S., and Hudson, L. C. (1998). Modulation of doxorubicin concentration by cyclosporin A in brain and testicular barrier tissues expressing P-glycoprotein in rats. J. Neurooncol. 37:45-54.
68. Horn, A., Kelly, P., and Westerink B. (1979). A prodrug of ADTN: Selectivity of dopaminergic action and brain levels of ADTN. Eur. J. Pharmacol. 60:95-99.
69. Huwyler. J., Wu, D., and Pardridge, W. M. (1996). Brain drug delivery of small molecules using immunoliposomes. Proc. Natl. Acad. Sci. USA 93:14164-14169.
70. Jones, D. R., Hall, S. D., Jackson, E. K., Branch, R. A., and Wilkinson, G. R. (1988). Brain uptake of benzodiazepines: Effects of lipophilicity and plasma protein binding. J. Pharmacol. Exp. Ther. 245:816-822.
71. Juliano, R. L., and Ling, V. (1976). A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim. Biophys. Acta 455:152-162.
72. Kreuter, J., Tauber, U., and Illi, V. (1979). Distribution and elimination of poly(methyl-2-14C-methacrylate) nanoparticle radioactivity after injection in rats and mice. J. Pharm. Sci. 68:1443-1447.
73. Lautier, D., Canitrot, Y., Deeley, R. G., and Cole, S. P. C. (1996). Multidrug-resistance mediated by the multidrug-resistance protein (MRP) gene. Biochem. Pharmacol. 52:967-977.
74. Lemaire, M., Bruelisauer, A., Guntz, P., and Sato, H. (1996). Dose-dependent brain penetration of SDZ PSC 833, a novel multidrug resistance-reversing cyclosporin, in rats. Cancer Chemother. Pharmacol. 38:481-486.
75. Le Petit, G. (1977). The pH dependent "lipid solubility" of drugs. Pharmazie 32:289-291.
76. Levin, V. A. (1980). Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J. Med. Chem. 23:682-684.
77. Levin, V. A., and Kabra, P. (1974). Effectiveness of the nitrosoureas as a function of their lipid solubility in the chemotherapy of experimental rat brain tumors. Cancer Chemother. Rep. 58:787-792.
78. Liebert, M., Wahl, R. L., Lawless, G., McKeever, P. E., Taren, J. A., Beierwaltes, W. H., and Brasswell, R. (1990). Direct sterotactic intracerebral injection of monoclonal antibodies and their fragments: A potential approach to brain tumor immunotherapy. Am. J. Physiol. Imag. 5:55-59.
79. Lombardino, J. G., Otterness, I. G., and Wiseman, E. H. (1975). Acidic antiinflammatory agents-correlations of some physical, pharmacological and clinical data. Arzneimittelforschung 25:1629-1635.
80. Mayer, S. E., Maickel, R. P., and Brodie, B. B. (1959). Kinetics of penetration of drugs and other foreign compounds into cerebrospinal fluid and brain. J. Pharmacol. 127:205-211.
81. McRae, A. C., and Kennedy, T. G. (1983). Selective permeability of the blood-uterine lumen barrier in rats: Importance of lipid solubility. Biol. Reprod. 29:886-894.
82. McRae-Degueurce, A., Hjorth, S., Dillon, D. L., Mason, D. W., and Tice, T. R. (1988). Implantable microencapsulated dopamine (DA): A new approach for slow-release DA delivery into brain tissue. Neurosci. Lett. 92:303-309.
83. Meulemans A., Vicart P., Mohler J., and Vulpillat M. (1988). Determination of antibiotic lipophilicity with a micromethod: Application to brain permeability in man and rats. Chemotherapy 34:90-95.
84. Meyers, M. B., Scotto, K. W., and Sirotnak, F. M. (1991). P-glycoprotein content and mediation of vincristine efflux: Correlation with the level of differentiation in luminal epithelium of mouse small intestine. Cancer Comm. 3:159-165.
85. Møllgård, K., Malinowska, D. H., and Saunders, N. R. (1976). Lack of correlation between tight junction morphology and permeability properties in developing choroid plexus. Nature 264:293-294.
86. Møllgard, K., Lauritzen, B., and Saunders, N. R. (1979). Double replica technique applied to choroid plexus from early foetal sheep: Completeness and complexity of tight junctions. J. Neurocytol. 8:139-149.
87. Nabeshema, S., and Reese, T. S. (1972). Barrier to proteins within the spinal meninges. J. Neuropathol. Exp. Neurol. 31:176-177.
88. Nabeshema, S., Reese, T. S., Landis, D. M. D., and Brightman, M. W. (1975). Junctions in the meninges and marginal glia. J. Comp. Neurol. 164:127-170.
89. Nagy, Z., Peters, H., and Huttner, I. (1984). Fracture faces of cell junctions in cerebral endothelium during normal and hyperosmotic conditions. Lab. Invest. 50:313-322.
90. Oldendorf, W. H. (1974). Lipid solubility and drug penetration of the blood brain barrier. Proc. Sac. Exp. Biol. Med. 147:813-815.
91. Olesen, S. P., and Crone, C. (1983). Electrical-resistance of muscle capillary endothelium. Biophys. J. 42:31-41.
92. Olivieri, N. F., Brittenham, G. M., Matsui, D., Berkovitch, M., Blendis, L. M., Cameron, R. G., McClelland, R. A., Liu, P. P., Templeton D. M., and Koren, G. (1995). Iron-chelation therapy with oral deferiprone in patients with thalassemia major. N. Engl. J. Med. 332:918-922.
93. Pardridge, W. M., Kang, Y. S., and Buciak, J. L. (1994). Transport of human recombinant brain-derived neurotrophic factor (BDNF) through the rat blood-brain barrier in vivo using vector-mediated peptide drug delivery. Pharm. Res. 11:738-746.
94. Pennock, G. D., Dalton, W. S., Roeske, W. R., Appleton, C. P., Mosley, K., Plezia, P., Miller, T. P., and Salmon, S. E. (1991). Systemic toxic effects associated with high dose verapamil infusion and chemotherapy administration. J. Natl. Cancer Inst. 83:105-110.
95. Ramsay, R. E., Hammond, E. J., Perchalski, R. J., and Wilder, B. J. (1979). Brain uptake of phenytoin, phenobarbital, and diazepam. Arch. Neural. 36:535-539.
96. Rapoport, S. I. (1976). Blood-Brain Barrier in Physiology and Medicine, Raven Press, New York.
97. Rapoport, S. I. (2000). Osmotic opening of the blood-brain barrier. Principles, mechanism, and therapeutic applications. Cell. Mol. Neurobiol. 20:217-230.
98. Rapoport, S. I., and Levitan, H. (1974). Neurotoxicity of X-ray contrast media: Relation to lipid solubility and blood-brain barrier permeability. Am. J. Roentgenol. 122:186-193.
99. Rapoport, S. I., and Robinson, P. J. (1986). Tight-junctional modification as the basis of osmotic opening of the blood-brain barrier. Ann. N.Y. Acad. Sci. 481:250-266.
100. Raviv, Y., Pollard, H. B., Brugemann, E. P., Pastan, I., and Gottesman, M. M. (1990). Photosensitized labeling of a functional multidrug transporter in living drug-resistant tumor-cells. J. Biol. Chem. 265:3975-3980.
101. Raymond, J. J., Robertson, D. M., and Dinsdale, H. B. (1986). Pharmacological modification of bradykinin induced breakdown of the blood-brain barrier. Can. J. Neurol. Sci. 13:214-220.
102. Regina, A., Koman, A., Center, M. S., Couraud, P. O., and Roux, F. (1997). Multidrug resistance-associated protein and P-glycoprotein expression in rat brain microvessel endothelial cells. J. Physiol. 505:57P.
103. Saija, A., Princi, P., Lanza, M., Scalese, M., Aramnejad, E., and De Sarro, A. (1995). Systemic cytokine administration can affect blood-brain barrier permeability in the rat. Life Sci. 56:775-784.
104. Sanovich, E., Bartus, R. T., Friden, P. M., Dean, R. L., Le, H. Q., and Brightman, M. W. (1995). Pathway across blood-brain barrier opened by the bradykinin agonist, RMP-7. Brain Res. 705:125-135.
105. Schinkel, A. H., Wagenaar, E., Mol, C. A., and van Deemter, L. (1996). P-Glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J. Clin. Invest. 97:2517-2524.
106. Schroeder, R. L., Weinger, M. B., Vakassian, L., and Koob, G. F. (1991). Methylnaloxonium diffuses out of the rat brain more slowly than naloxone after direct intracerebral injection. Neurosci. Lett. 121:173-177.
107. Schroeder, U., Sommerfeld, P., and Sabel, B. A. (1998). Efficacy of oral dalargin-loaded nanoparticle delivery across the blood-brain barrier. Peptides 19:777-780.
108. Seiler, P. (1974). Interconversion of lipophilicities from hydrocarbon/water systems into the octanol/ water system. Eur. J. Med. Chem. 9:473-479.
109. Slapak, C. A., Martell, R. L., Terashima, M., and Levy, S. B. (1996). Increased efflux of vincristine, but not of daunorubicin, associated with the murine multidrug resistance protein (MRP). Biochem. Pharmacol. 52:1569-1576.
110. Smith, Q. R. (1993). Drug delivery to brain and the role of carrier-mediated transport. Adv. Exp. Med. Biol. 331:83-93.
111. Stella, V. J., Charman, W. N. A., and Naringrekar, V. H. (1985). Prodrugs, do they have advantages in clinical practice. Drugs 29:455-473.
112. Sutherland, W. A. (1905). A dynamical theory of diffusion for non-electrolytes and the molecular mass of albumin. Phil. Mag. 9:781-785.
113. Takada, T., Greig, N. H., Vistica, D. T., Rapoport, S. I., and Smith, Q. R. (1991). Affinity of antineoplastic amino acid drugs for the large neutral amino acid transporter of the blood-brain barrier. Cancer Chemother. Pharmacol. 29:89-94.
114. Tatsuta, T., Naito, M., Oh-hara, T., Sugawara, I., and Tsuruo, T. (1992). Functional involvement of P-glycoprotein in blood-brain barrier. J. Biol. Chem. 267:20383-20391.
115. Tennyson, V. M., and Pappas, G. D. (1968). The fine structure of the choroid plexus: Adult and developmental stages. In Lajtha A., and Ford D. H. (eds.), Progress in Brain Research: Brain Barrier Systems, Vol. 29, Elsevier, Amsterdam, pp. 63-85.
116. Thiebaut, F., Tsuruo, T., Hamada, H., Gottesmann, M. M., Pastan, I., and Willingham, M. C. (1989). 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.
117. Tokes, Z. A., St Peteri, A. K., and Todd, J. A. (1980). Availability of liposome content to the nervous system. Liposomes and the blood-brain barrier. Brain Res. 188:282-286.
118. Tsuji, A., Tamai, I., Sakata, A., Tenda, Y., and Terasaki, T. (1993). Restricted transport of cyclosporin A across the blood-brain barrier by a multidrug transporter, P-glycoprotein. Biochem. Pharmacol. 46:1096-1099.
119. Umezawa, F., and Eto, Y. (1988). Liposome targeting to mouse brain: Mannose as a recognition marker. Biochem. Biophys. Res. Commun. 153:1038-1044.
120. Wolburg, H., Neuhaus, J., Kniesel, U., Krauβ, B., Schmid, E., Öcalan, M., Farrell, C., and Risau, W. (1994). Modulation of tight junction structure in blood-brain barrier endothelial cells. J. Cell Sci. 107:1347-1357.
121. 2 receptor histamine antagonists. J. Med. Chem. 31:656-671.