Skip to main content
SpringerLink
Log in

Determinants of Passive Drug Entry into the Central Nervous System

  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

1. The blood–brain barriers restrict the passive diffusion of many drugs into the brain and constitute a significant obstacle in the pharmacological treatment of central nervous system diseases and disorders. The degree of restriction they impose is variable, with some lipid-insoluble drugs effectively excluded from the brain, while many lipid-soluble drugs do not appear to be subject to any restriction.

2. The ease with which any particular drug diffuses across the blood–brain barrier is determined largely by the number and strength of intermolecular forces “holding” it to surrounding water molecules. By quantifying the molecular features that contribute to these forces, it is possible to predict the in vivo blood–brain barrier permeability of a drug from its molecular structure. Dipolarity, polarizability, and hydrogen bonding ability are factors that appear to reduce permeability, whereas molecular volume (size) and molar refraction are associated with increased permeability.

3. Increasing the passive entry of “restricted” drugs into the central nervous system can be achieved by disrupting the blood–brain barrier (increased paracellular diffusion) or by modifying the structure of “restricted” drugs to temporarily or permanently increase their lipid solubility (increased transcellular permeability).

4. Competitive inhibition of outwardly directed active efflux mechanisms (P-glycoprotein and MRP, the multidrug resistance-related protein) can also significantly increase the accumulation of certain drugs within the central nervous system.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  • Abbott, N. J. (2000). Inflammatory mediators and modulation of blood-brain barrier permeability. Cell. Mol. Neurobiol. 20:131-147.

    Google Scholar 

  • Abraham, M. H. (1993). Scales of solute hydrogen bonding: Their construction and application to physicochemical and biochemical processes. Chem. Soc. Rev. 22:73-83.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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 Dlog P parameter of Seiler. J. Pharm. Sci. 83:1085-1100.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • Anderson, B. D. (1996). Prodrugs for improved CNS delivery. Adv. Drug Deliv. Rev. 19:171-202.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • Becker, H., and Quadbeck, G. (1952a). Tierexperimentelle Untersuchungen u. d. Funktionweise der Blut Hirnschranke. Z. Naturforsch. 7B:493-497.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • Bradbury, M. W. B. (1979). The Concept of a Blood-Brain Barrier, John Wiley and Sons, New York.

    Google Scholar 

  • Brightman, M. W. (1977). Morphology of the blood-brain barrier interfaces. Exp. Eye Res. 25:1-25.

    Google Scholar 

  • Brightman, M. W. (1992). Ultrastructure of brain endothelium. Hand. Exp. Pharm. 103:1-22.

    Google Scholar 

  • Brightman, M. W., and Reese, T. S. (1969). Junctions between intimately apposed cell membranes in the vertebrate brain. J. Cell Biol. 40:648-677.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • Crone, C., and Christensen, O. (1981). Electrical resistance of a capillary endothelium. J. Gen. Physiol. 77:349-371.

    Google Scholar 

  • Crone, C., and Olesen, S. P. (1981). The electrical-resistance of brain capillary endothelium. J. Physiol. 316:53-54.

    Google Scholar 

  • Crone, C., and Olesen, S. P. (1982). Electrical-resistance of brain micro-vascular endothelium. Brain Res. 241:49-55.

    Google Scholar 

  • 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.

    Google Scholar 

  • Davson, H., and Danielli, J. F. (1943). The Permeability of Natural Membranes, Cambridge University Press, Cambridge.

    Google Scholar 

  • Davson, H., and Segal, M. B. (1996). Physiology of the CSF and Blood-Brain Barriers, CRC Press, Boca Raton, FL.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • Einstein, A. (1905). Uber die von der molekularkinetischen theorie der Earme geforderte bewegung von in ruhenden flussigkeiten suspendierten teilchen. Ann. Phys. 17:549-560.

    Google Scholar 

  • 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.

    Google Scholar 

  • Endicott, J. A., and Ling, V. (1989). The biochemistry of P-glycoprotein mediated multidrug resistance. Annu. Rev. Biochem. 58:137-171.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • Felgenhauer, K. (1974). Protein size and cerebrospinal fluid. Klin. Wochenschrift. 52:1158-1164.

    Google Scholar 

  • 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.

    Google Scholar 

  • Ferguson, R. K., and Woodbury, D. M. (1969). Penetration of 14C-inulin and 14C-sucrose into brain, cerebrospinal fluid, and skeletal muscle of developing rats. Exp. Brain Res. 7:181-194.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain. Cancer Res. 58:672-684.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • Gottesman, M. M., and Pastan, I. (1993). Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu. Rev. Biochem. 62:385-427.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • Greenwood, J. (1992). Experimental manipulation of the blood-brain and blood-retinal barriers. Hand. Exp. Pharmacol. 103:461-486.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • Hansch, C., and Leo, A. (1979). Substituent Constants for Correlation Analysis in Chemistry and Biology, John Wiley and Sons, New York.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • Healy, D. P., and Orlowski, M. (1992). Immunocytochemical localization of endopeptidase 24.15 in rat brain. Brain Res. 571:121-128.

    Google Scholar 

  • Higgins, C. F., and Gottesman, M. M. (1992). Is the multidrug transporter a flippase. TIBS. 17:18-21.

    Google Scholar 

  • 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 Pglycoprotein in rats. J. Neurooncol. 37:45-54.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • Le Petit, G. (1977). The pH dependent ''lipid solubility'' of drugs. Pharmazie 32:289-291.

    Google Scholar 

  • Levin, V. A. (1980). Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J. Med. Chem. 23:682-684.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • Lombardino, J. G., Otterness, I. G., and Wiseman, E. H. (1975). Acidic antiinflammatory agentscorrelations of some physical, pharmacological and clinical data. Arzneimittelforschung 25:1629-1635.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • Møllgård, 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.

    Google Scholar 

  • Nabeshema, S., and Reese, T. S. (1972). Barrier to proteins within the spinal meninges. J. Neuropathol. Exp. Neurol. 31:176-177.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • Oldendorf, W. H. (1974). Lipid solubility and drug penetration of the blood brain barrier. Proc. Soc. Exp. Biol. Med. 147:813-815.

    Google Scholar 

  • Olesen, S. P., and Crone, C. (1983). Electrical-resistance of muscle capillary endothelium. Biophys. J. 42:31-41.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • Ramsay, R. E., Hammond, E. J., Perchalski, R. J., and Wilder, B. J. (1979). Brain uptake of phenytoin, phenobarbital, and diazepam. Arch. Neurol. 36535-539

    Google Scholar 

  • Rapoport, S. I. (1976). Blood-Brain Barrier in Physiology and Medicine, Raven Press, New York.

    Google Scholar 

  • Rapoport, S. I. (2000). Osmotic opening of the blood-brain barrier. Principles, mechanism, and therapeutic applications. Cell. Mol. Neurobiol. 20:217-230.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • Regina, A., Koman, A., Center, M. S., Couraud, P. O., and Roux, F. (1997). Multidrug resistanceassociated protein and P-glycoprotein expression in rat brain microvessel endothelial cells. J. Physiol. 505:57P.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • Schinkel, A. H., Wagenaar, E., Mol, C. A., and van Deemter, L. (1996). P-Glycoprotein in the bloodbrain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J. Clin. Invest. 97:2517-2524.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • Seiler, P. (1974). Interconversion of lipophilicities from hydrocarbon/water systems into the octanol/ water system. Eur. J. Med. Chem. 9:473-479.

    Google Scholar 

  • 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.

    Google Scholar 

  • Smith, Q. R. (1993). Drug delivery to brain and the role of carrier-mediated transport. Adv. Exp. Med. Biol. 331:83-93.

    Google Scholar 

  • Stella, V. J., Charman, W. N. A., and Naringrekar, V. H. (1985). Prodrugs, do they have advantages in clinical practice. Drugs 29:455-473.

    Google Scholar 

  • Sutherland, W. A. (1905). A dynamical theory of diffusion for non-electrolytes and the molecular mass of albumin. Phil. Mag. 9:781-785.

    Google Scholar 

  • 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.

    Google Scholar 

  • Tatsuta, T., Naito, M., Oh-hara, T., Sugawara, I., and Tsuruo, T. (1992). Functional involvement of Pglycoprotein in blood-brain barrier. J. Biol. Chem. 267:20383-20391.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • Umezawa, F., and Eto, Y. (1988). Liposome targeting to mouse brain: Mannose as a recognition marker. Biochem. Biophys. Res. Commun. 153:1038-1044.

    Google Scholar 

  • Wolburg, H., Neuhaus, J., Kniesel, U., Kraub, 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.

    Google Scholar 

  • Young, R. C., Mitchell, R. C., Brown, T. H., Ganellin, C. R., Griffiths, R., Jones, M., Rana, K. K., Saunders, D., Smith, I. R., Sore, N. E., and Wilkes, T. J. (1988). Development of a new physicochemical model for brain penetration and its application to the design of centrally acting H2 receptor histamine antagonists. J. Med. Chem. 31:656-671.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Anatomy and Physiology, University of Tasmania, GPO Box 252-24, Hobart, 7001, Tasmania, Australia

    M. D. Habgood

  2. Biomedical Sciences Division, King's College London, Strand, London, WC2R 2LS, United Kingdom

    D. J. Begley & N. J. Abbott

Authors
  1. M. D. Habgood
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. J. Begley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. J. Abbott
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Habgood, M.D., Begley, D.J. & Abbott, N.J. Determinants of Passive Drug Entry into the Central Nervous System. Cell Mol Neurobiol 20, 231–253 (2000). https://doi.org/10.1023/A:1007001923498

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1007001923498

Search

Navigation