The Role of Plasma Protein Binding in Drug Delivery to Brain

  • Quentin R. Smith
  • Carolyn Fisher
  • David D. Allen


Many factors influence drug activity in brain. One of the most important is the ability of a drug to gain access to brain following systemic administration by passage across the blood-brain barrier (BBB). The BBB is formed at the cerebral capillaries by a continuous layer of endothelial cells that are joined together by high resistance tight junctions (Pardridge, 1998). These tight junctions effectively seal off the aqueous paracellular channels between brain endothelial cells, so that if a drug is to gain access to brain it must either be of the appropriate lipid solubility, hydrogen bonding capacity, and size to readily dissolve and diffuse across the lipophilic endothelial cell membranes (Habgood et al.,2000) or be transported across the endothelium by any of 20 or more active or facilitated carrier systems which are expressed in brain capillaries at high levels (Smith et al.,1995).


Plasma Protein Binding Free Fraction Brain Perfusion Brain Uptake Brain Capillary 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Deane, R. and Bradbury, M.W.B., 1990, Transport of lead-203 at the blood-brain barrier during short cerebrovascular perfusion with saline in the rat. J Neurochem 54: 905–914.PubMedCrossRefGoogle Scholar
  2. Dubey, R.K., McAllister, C.B., Inoue, M., and Wilkinson, G.R., 1989, Plasma binding and transport of diazepam across the blood-brain barrier: no evidence for in vivo enhanced dissociation. J. Clin. Invest. 84: 1155–1159.PubMedCrossRefGoogle Scholar
  3. Fenerty, C.A., and Lindup, W.E., 1989, Brain uptake of L-tryptophan and diazepam: the role of plasma protein binding. J. Neurochem. 53: 416–422.PubMedCrossRefGoogle Scholar
  4. Fukui, S., Schwarcz, R., Rapoport, S.I., Takada, Y., and Smith, Q.R., 1991, Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism. J. Neurochem. 56: 2007–2017.PubMedCrossRefGoogle Scholar
  5. Habgood, M.D., Begley, D.J., and Abbott, N.J., 2000, Determinants of passive drug entry into the central nervous system. Cell. Mol. Neurobiol. 20: 231–253.PubMedCrossRefGoogle Scholar
  6. Hansch, C., and Leo, A., 1995, Exploring QSAR. American Chemical Society, Washington, D.C.Google Scholar
  7. Ives, N.K., and Gardiner, R.M., 1990, Blood-brain barrier permeability to bilirubin in the rat studied using intracarotid bolus injection and in situ brain perfusion techniques. Pediatr. Res. 27: 436–441.PubMedCrossRefGoogle Scholar
  8. Jezequel, S.G., 1992, Central nervous system penetration of drugs: importance of physicochemical properties. In Progress in Drug Metabolism (G.G. Gibson, ed.); Taylor and Francis, London, pp. 141–178.Google Scholar
  9. 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. JPET 245: 816–822.Google Scholar
  10. Kragh-Hansen, U., 1981, Molecular aspects of ligand binding to serum albumin. Pharm. Rev. 33: 17–53.PubMedGoogle Scholar
  11. Levitan, H., Ziylan, Z., Smith, Q.R., Takasato, Y., and Rapoport, S.I., 1984, Brain uptake of a food dye, erythrosin B, prevented by plasma protein binding. Brain Res. 322: 131–134.PubMedCrossRefGoogle Scholar
  12. Lin, T-H., and Lin, J.H., 1990, Effects of protein binding and experimental disease states on brain uptake of benzodiazepines in rats. JPET 253: 45–50.Google Scholar
  13. Morris, C.A., Keith, A.B., Edwardson, J.A., and Pullen, R.G.L., 1992, Uptake and distribution of iron and transferrin in the adult rat brain. J. Neurochem. 59: 300–306.PubMedCrossRefGoogle Scholar
  14. Murphy, V.A., and Rapoport, S.I., 1992, Brain transfer coefficients for 67Ga: comparison to 55Fe and effect of calcium deficiency. J. Neurochem. 58: 898–902.PubMedCrossRefGoogle Scholar
  15. Pardridge, W.M., 1998, CNS drug design based on principles of blood-brain barrier transport. J. Neurochem. 70: 1781–1792..PubMedCrossRefGoogle Scholar
  16. Pardridge, W.M., Eisenberg, J., and Cefalu, W.T., 1985, Absence of albumin receptor on brain capillaries in vivo or in vitro. Am. J. Physiol. 249: E264–E267.PubMedGoogle Scholar
  17. Pardridge, W.M., and Landaw, E.M., 1984, Tracer kinetic model of blood-brain barrier transport of plasma protein-bound ligands. J. Clin. Invest. 74: 745–752.PubMedCrossRefGoogle Scholar
  18. Pardridge W.M. and Mietus, L.J., 1980, Palmitate and cholesterol transport through the blood-brain barrier. J. Neurochem. 34: 463–466.PubMedCrossRefGoogle Scholar
  19. Peters, T., 1996, All about albumin: biochemistry, genetics, and medical applications. Academic Press, San Diego.Google Scholar
  20. Rabin, O., Hegedus, L., Bourre, J-M., and Smith, Q.R., 1993, Rapid brain uptake of manganese (II) across the blood-brain barrier. J. Neurochem. 61: 509–517.PubMedCrossRefGoogle Scholar
  21. Robinson P.J., Noronha, J., DeGeorge J J., Freed L.M., Nariai T., and Rapoport, S.I., 1992, A quantitative method for measuring regional in vivo fatty-acid incorporation into and turnover within brain phospholipids: review and critical analysis. Brain Res. Rev. 17: 187–214.PubMedCrossRefGoogle Scholar
  22. Robinson, P.J., and Rapoport, S.I., 1986, Kinetics of protein binding determine rates of uptake of drugs by brain. Am. J. Physiol. 251: R1212–R1220.PubMedGoogle Scholar
  23. Smith, Q.R., 1995, Carrier-mediated drug transport at the blood-brain barrier and the potential for drug targeting to the brain. In New Concepts of a Blood-Brain Barrier (J. Greenwood, et. al., eds.); Plenum Press, New York, pp. 265–276.Google Scholar
  24. Smith Q. R., 1996, Brain perfusion systems for studies of drug uptake and metabolism in the central nervous system. Pharmaceut. Biotech. 8: 285–308.Google Scholar
  25. Smith, Q.R., and Nagura, H., 2001, Fatty acid uptake and incorporation in brain. J. Mol. Neurosci. 16: 81–86.CrossRefGoogle Scholar
  26. Smith, Q.R., Fisher, C., Allen, D., and Oki, J.: Development of a novel screening method to predict brain availability to drugs that bind highly to plasma proteins. Pharm. Sci. (Supplement) 1: 3115, 1998.Google Scholar
  27. Smith, Q.R., Fisher, C.R., and Liu, X.: Brain uptake of the lipophilic anticancer drug chlorambucil-Limitation by plasma protein binding. Pharm. Sci. (Supplement) 2: 2106, 200Google Scholar
  28. Spector, R., 1988, Fatty acid transport through the blood-brain barrier. J. Neurochem. 50: 639–643.PubMedCrossRefGoogle Scholar
  29. Svenson, A., Holmer, E., and Andersson, L-O., 1974, A new method for the measurement of dissociation rates for complexes between small ligands and proteins as applied to the palmitate and bilirubin complexes with serum albumin. BBA 342: 54–59.PubMedCrossRefGoogle Scholar
  30. Takasato, Y., Rapoport, S.I., and Smith, Q.R., 1984, An in situ brain perfusion technique to study cerebrovascular transport in the rat. Am. J. Physiol. 246: H484–H493.Google Scholar
  31. Tanaka, H., and Mizojiri, K., 1999, Drug-protein binding and blood-brain barrier permeability. J. Pharmacol. Exp. Ther. 288: 912–918.PubMedGoogle Scholar
  32. Tillement, J-P., Houin, G., Zini, R., Urien, S., Albengres, E., Barre, J., Lecomte, M., D’Athis, P., and Sebille, B., 1984, The binding of drugs to blood plasma macromolecules: recent advances and therapeutic significance. In Advances in Drug Research 13: 60–94.Google Scholar
  33. Wosilait, W. D., and Soler-Argilaga, C., 1975, A theoretical analysis of the multiple binding of palmitate by bovine serum albumin: the relationship to uptake of free fatty acids by tissues. Life Sci. 17: 159–166.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Quentin R. Smith
    • 1
  • Carolyn Fisher
    • 1
  • David D. Allen
    • 1
  1. 1.Department of Pharmaceutical SciencesTexas Tech University Health Sciences CenterAmarilloUSA

Personalised recommendations