Skip to main content
Log in

Drug transport across the blood — brain barrier

II. Experimental techniques to study drug transport

  • Reviews
  • Published:
Pharmaceutisch Weekblad Aims and scope Submit manuscript

Abstract

This is part II of a review on the transport of drugs across the blood-brain barrier. In this part, the emphasis is on the various experimental techniques that can be used to characterize the blood — brain barrier transport of drugs. Generally speaking, three approaches can be distinguished:in vitro techniques using isolated brain capillaries, cerebrovascular endothelial cells in primary culture or endothelium-derived cell lines;in vivo techniques (both single-passage and multi-passage techniques) andin situ perfusion techniques. Each of these techniques has specific advantages and disadvantages associated with it. Therefore, in many instances, a combination of different approaches is needed to study the fundamental aspects of drug transport across the blood-brain barrier.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Van Bree JBMM, De Boer AG, Danhof M, Breimer DD. Drug transport across the blood—brain barrier. I. Anatomical and physiological aspects. Pharm Weekbl [Sci] 1992;14(5):305–10.

    Google Scholar 

  2. Siakotos AN, Rouser G, Fleischer S. Isolation of highly purified human and bovine brain endothelial cells and nuclei and their phospholipid composition. Lipids 1969;4:234–9.

    PubMed  Google Scholar 

  3. Brendel K, Meezan E, Carlson EC. Isolated brain microvessels. A purified metabolically active preparation from bovine cerebral cortex. Science 1974;185:953–5.

    PubMed  Google Scholar 

  4. Meresse S, Dehouck M-P, Delorme P, Bensaid M, Tauber J-P, Delbart C, et al. Bovine brain endothelial cells express tight junctions and monoamine oxidase activity in long-term culture. J Neurochem 1989;53(5):1363–71.

    PubMed  Google Scholar 

  5. Goldstein GW, Wolinski JS, Csejtey J, Diamond I. Isolation of metabolically active capillaries from rat brain. J Neurochem 1975;25:715–17.

    PubMed  Google Scholar 

  6. Panula P, Joo F, Rechardt L. Evidence for the presence of viable endothelial cells in cultures derived from dissociated rat brain. Experientia 1978;34:95–7.

    Article  PubMed  Google Scholar 

  7. Hjelle JT, Baird-Lambert J, Cardinale G, Spector S, Udenfried S. Isolated microvessels the blood—brain barrierin vitro. Proc Natl Acad Sci USA 1978;75:4544–8.

    PubMed  Google Scholar 

  8. De Bault LE, Kahn LE, Frommes SP, Cancilla PA. Cerebral microvessels and derived cells in tissue culture. Isolation and preliminary characterisation. In Vitro 1979;15:473–87.

    PubMed  Google Scholar 

  9. Williams SK, Gillis JF, Matthews MA, Wagner RC, Bitenski MW. Isolation and characterization of brain endothelial cells. Morphology and enzyme activity. J Neurochem 1980;35:374–81.

    PubMed  Google Scholar 

  10. Phillips P, Kumar P, Kumar S, Waghe M. Isolation and characterization of endothelial cells from rat and cow brain white matter. J Anat 1979;129:261–72.

    PubMed  Google Scholar 

  11. Spatz M, Bembry J, Dodson RF, Hervonen H, Murray MR. Endothelial cell cultures derived from isolated cerebral microvessels. Brain Res 1980;191:577–82.

    Article  PubMed  Google Scholar 

  12. Bowman PD, Betz AL, Ar D, Wolinsky JS, Penney JB, Shivers RR, Goldstein GW. Primary culture of capillary endothelium from rat brain. In Vitro 1981;17:353–62.

    PubMed  Google Scholar 

  13. Bowman PD, Betz AL, Goldstein GW. Primary culture of microvascular endothelial cells from bovine retina. Selective growth using fibronectin coated substrate and plasma derived serum. In Vitro 1982;18:626–32.

    PubMed  Google Scholar 

  14. Diglio CA, Grammas P, Giacomelli F, Wiener J. Primary culture of rat cerebral microvascular endothelial cells. Lab Invest 1982;46:554–63.

    PubMed  Google Scholar 

  15. Bowman PD, Ennis SR, Rarey KE, Betz AL, Goldstein GW. Brain microvessel endothelial cells in tissue culture. A model for study of blood—brain barrier permeability. Ann Neurol 1983;14:396–402.

    Article  PubMed  Google Scholar 

  16. Audus KL, Borchardt RT. Characterization of anin vitro blood—brain barrier model system for studying drug transport and metabolism. Pharm Res 1986;3:81–7.

    Article  Google Scholar 

  17. Rim S, Audus KL, Borchardt RT. Relationship of octanol/buffer and octanol/water partition coefficients to transcellular diffusion across brain microvessel endothelial cell monolayers. Int J Pharm 1986;32:79–84.

    Article  Google Scholar 

  18. Bottaro D, Shepro D, Hechtman HB. Heterogeneity of intimal and microvessel endothelial cell barriersin vitro. Microvasc Res 1986;32:389–98.

    Article  PubMed  Google Scholar 

  19. Kempski O, Villacara A, Spatz M, Dodson RF, Corn C, Merkel N, et al. Cerebrovascular endothelial permeability.In vitro studies. Acta Neuropathol 1987;74:329–34.

    Article  PubMed  Google Scholar 

  20. DeBault LE, Henriquez E, Hart MN, Cancilla PA. Cerebral microvessels and derived cells in tissue culture. II. Establishment, identification and preliminary characterization of an endothelial cell line. In Vitro 1981;17:480–94.

    PubMed  Google Scholar 

  21. Caspers ML, Diglio CA. Expression of gamma-glutamyl transpeptidase in a transformed rat cerebral endothelial cell line. Biochim Biophys Acta 1984;803:1–6.

    Article  PubMed  Google Scholar 

  22. Soric J, Gordon JA. Vanadate stimulates the pp60v-src tyrosine kinase activity in intact transformed rat cerebral endothelial cells. Period Biol 1988;90:413–9.

    Google Scholar 

  23. Tonsch U, Bauer HC. Isolation, characterization and long-term cultivation of porcine and murine cerebral capillary endothelial cells. Microvasc Res 1989;37:148–61.

    Article  PubMed  Google Scholar 

  24. Minakawa T. Long-term culture of microvascular endothelial cells derived from mongolian gerbil brain. Stroke 1989;20:947–51.

    PubMed  Google Scholar 

  25. Hennig B, Boissonneault GA, Glauert HP. Effects of serum type on growth and permeability properties of cultured endothelial cells. Exp Cell Res 1989;181:589–96.

    Article  PubMed  Google Scholar 

  26. Robinson RA, Teneyck CJ, Hart MN. Growth control in cerebral microvessel-derived endothelial cells. Brain Res 1986;384:114–20.

    Article  PubMed  Google Scholar 

  27. Tao-Cheng JH, Nagy Z, Brightman MW. Tight junctions of brain endotheliumin vitro are enhanced by astrocytes. J Neurosci 1987;7:3293–9.

    PubMed  Google Scholar 

  28. Betz AL, Goldstein GW. Polarity of the blood—brain barrier. Neutral amino acid transport into isolated brain capillaries. Science 1978;202:225–7.

    PubMed  Google Scholar 

  29. Betz AL, Firth JA, Goldstein GW. Polarity of the blood—brain barrier. Distribution of enzymes between the luminal and the abluminal membranes of brain capillary endothelial cells. Brain Res 1980;192:17–28.

    Article  PubMed  Google Scholar 

  30. Pardridge WM, Mietus LJ. Enkephalin and the blood—brain barrier. Studies of binding and degradation in isolated brain capillaries. Endocrinology 1981;109:1138–42.

    PubMed  Google Scholar 

  31. Ghersi-Egea JF, Minn A, Siest G. A new aspect of the protective function of the blood—brain barrier. Activities of four drug-metabolizing enzymes in isolated rat brain. Life Sci 1988;42:2515–23.

    Article  PubMed  Google Scholar 

  32. White FP, Dutton GR, Norenberg MD. Microvessels isolated from rat brain. Localization of astrocyte processes by immunohistochemical techniques. J Neurochem 1981;36:328–32.

    PubMed  Google Scholar 

  33. Lidinski WA, Drewes LR. Characterization of the blood—brain barrier. Protein composition of the capillary endothelial cell membrane. J Neurochem 1983;41:1341–8.

    PubMed  Google Scholar 

  34. Baranczyk-Kuzma A, Audus KL, Borchardt RT. Catecholamine-metabolizing enzymes of bovine brain microvessel endothelial cell monolayers. J Neurochem 1986;46:1956–60.

    PubMed  Google Scholar 

  35. Van Bree JBMM, Audus KL, Borchardt RT. Carriermediated transport of baclofen across monolayers of bovine brain endothelial cells in primary culture. Pharm Res 1988;5:369–71.

    Article  PubMed  Google Scholar 

  36. Olson JJ, Poor MM, Beck DW. Methylprednisolone reduces the bulk flow of water across anin vitro blood—brain barrier. Brain Res 1988;439:259–65.

    Article  PubMed  Google Scholar 

  37. Audus KL, Shinogle JA, Guillot FL, Holthaus SR. Aluminum effects the brain microvessel endothelial cell monolayer permeability. Int J Pharm 1988;45:249–57.

    Article  Google Scholar 

  38. Villacara A, Spatz M, Dodson RF, Corn C, Bembry J. Effect of arachidonic acid on cultured cerebromicrovascular endothelium. Permeability, lipid peroxidation and membrane fluidity. Acta Neuropathol 1989;78:310–6.

    Article  PubMed  Google Scholar 

  39. Crone C. The permeability of capillaries in various organs as determined by the use of the indicator dilution method. Acta Physiol Scand 1963;58:292–305.

    PubMed  Google Scholar 

  40. Rapoport SJ. Permeability and osmotic properties of the blood—brain barrier. In: Rapoport SJ, ed. Blood— brain barrier in physiology and medicine. New York: Raven Press, 1976:87.

    Google Scholar 

  41. Hertz MM, Paulson OB. Heterogeneity of cerebral capillary flow in man and its consequences for estimation of blood—brain barrier permeability. J Clin Invest 1980;65:1145–51.

    PubMed  Google Scholar 

  42. Sawada Y, Patlak CS, Blasberg RG. Kinetic analysis of cerebrovascular transport based on indicator diffusion technique. Am J Physiol 1989;256:H794–812.

    PubMed  Google Scholar 

  43. Oldendorf WH. Measurement of radiolabelled substances using a tritiated water internal standard. Brain Res 1970;24:372–6.

    PubMed  Google Scholar 

  44. Bradbury MWB, Patlak CS, Oldendorf WH. Analysis of brain uptake and loss of radiotracers after intracarotid injection. Am J Physiol 1975;229:1110–5.

    PubMed  Google Scholar 

  45. Fenstermacher JD, Blasberg RG, Patlak CS. Methods for quantifying the transport of drugs across the blood—brain systems. Pharmacol Ther 1981;14:217–48.

    Article  PubMed  Google Scholar 

  46. Kastin AJ, Zadina JE, Banks WA, Graf MV. Misleading concepts in the field of brain peptides. Peptides 1984;5:249–53.

    Article  PubMed  Google Scholar 

  47. Smith QR. Quantitation of blood—brain barrier permeability. In: Neuwelt EA, ed. Implications of the blood—brain barrier and its manipulation. Vol. 1. Basic science aspects. New York: Plenum Press, 1989:85–118.

    Google Scholar 

  48. Rapoport SI, Ohno K, Pettigrew KD. Drug entry into the brain. Brain Res 1979;172:354–9.

    Article  PubMed  Google Scholar 

  49. Preston E, Haas N. Defining the lower limits for blood—brain barrier permeability. Factors affecting the magnitude and interpretation of permeability-area products. J Neurosci Res 1986;16:709–19.

    Article  PubMed  Google Scholar 

  50. Brodie BB, Kurz H, Shanker LS. The importance of dissociation constant and lipid solubility in influencing the passage of drugs into the central nervous system. J Pharmacol Exp Ther 1960;130:519–28.

    Google Scholar 

  51. Patlak CS, Blasberg RG, Fenstermacher JD. Graphic evaluation of blood to brain transfer constants from multiple time uptake data. J Cerebral Blood Flow Metab 1983;3:1–7.

    Google Scholar 

  52. Crone C, Levitt DG. Capillary permeability to small solutes. In: Renkin EM, Michel CC, eds. Handbook of physiology. Vol. 4. Part 1. Bethesda: American Physiological Society, 1984:411–66.

    Google Scholar 

  53. Patlak CS, Blasberg RG. Graphic evaluation of blood to brain transfer constants from multiple time uptake data: generalizations. J Cerebral Blood Flow Metab 1985;5:584–90.

    Google Scholar 

  54. Van Bree JBMM, Baljet AV, Van Geyt A, De Boer AG, Danhof M, Breimer DD. The unit impulse response procedure for the pharmacokinetic evaluation of drug entry into the central nervous system. J Pharmacokinet Biopharm 1989;17:441–62.

    Article  PubMed  Google Scholar 

  55. Takasato Y, Rapoport SI, Smith QR. Anin situ brain perfusion technique to study cerebrovascular transport in the rat. Am J Physiol 1984;247:H484–93.

    PubMed  Google Scholar 

  56. Zlokovic BV, Begley DJ, Djuricic BM, Mitrovic DM. Measurement of solute transport in the perfused guinea pig brain. Method application toN-methyl-α-aminoisobutyric acid. J Neurochem 1986;46:1444–51.

    PubMed  Google Scholar 

  57. Risau W, Dingler A, Albrecht U, Dehouck M-P, Cecchelli R. Blood — brain barrier pericytes are the main source ofγ-glutamyl transpeptidase activity in brain capillaries. J Neurochem 1992;58:667–72.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Van Bree, J.B.M.M., De Boer, A.G., Danhof, M. et al. Drug transport across the blood — brain barrier. Pharmaceutisch Weekblad Scientific Edition 14, 338–348 (1992). https://doi.org/10.1007/BF01970169

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01970169

Keywords

Navigation