Abstract
The transport of drugs to the central nervous system (CNS) from the circulating blood requires them to cross either the blood-brain barrier (BBB) or blood-cerebrospinal fluid barrier (BCSFB) (Fig. 1). The BBB, which is formed by complex tight junctions of brain capillary endothelial cells, separates the circulating blood from the interstitial fluid in the brain. Although the BCSFB is also formed by the complex tight junctions of the choroid plexus epithelial cells and separates the blood from the cerebrospinal fluid (CSF), the area of BBB is about 5,000-times greater than that of the BCSFB. There is an ependymal layer between the brain parenchymal cells and CSF, but this does not act as a barrier to prevent diffusion of drugs from the CSF to the CNS. Nevertheless, the diffusion rate of drugs between CSF and brain parenchymal cells is very slow. Although the cellular volume of the brain capillaries is only 0.1~0.2% of the entire brain, the total length of the brain capillaries is about 600 km and the total surface area is about 9–12 m2 in humans. As the brain capillaries are ramified, like the network in the cerebrum at intervals of about 40 gm, small molecules such as nutrients immediately diffuse into the brain parenchymal ‘cells following their passage across the BBB. In general, the BBB is a main route for drug transport from the blood to the CNS. In other words, a high drug concentration in the CSF is not necessary if the drug is able to cross the BBB very efficiently.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
Similar content being viewed by others
References
Oldendolf, W.H. Measurement of brain uptake of radiolabeled substances using a tritiated water internal standard. Brain. Res. 1970; 24: 372.
Oldendolf, W.H. Brain uptake of radiolabeled amino acids, amines and hexose after arterial injection. Am. J. Physiol. 1971; 221: 1629.
Terasaki, T., and Hosoya, K. The blood-brain barrier efflux transporters as a detoxifying system for the brain. Adv. Drug Deliv. Rev. 1999; 36: 195.
Pardridge, W.M., Boado, R.J., Farrell, and C.R. Brain-type glucose transporter (GLUT-1) is selectively localized to the blood-brain barrier. J. Biol. Chem. 1990; 265: 18035.
Augus, D.B., Gambhir, S.S., Pardridge, W.M., Spielholz, C., Baselga, J., Vera, J.C., and Golde, D.W. Vitamin C crosses the blood-brain barrier in the oxidized form through the glucose transporters. J. Clin. Invest. 1997; 100: 2842.
Tamai, I., Takanaga, H., Maeda, H., Sai, Y., Ogihara, T., Higashida, H., and Tsuji, A. Participation of proton-cotransporter, MCTI, in the intestinal transport of monocarboxylic acids. Biochem. Biophys. Res. Commun. 1995; 214: 482.
Kanai, Y., Segawa, H., Miyamoto, K., Uchino,-H., Takeda, E., and Endou, H. Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98). J. Biol. Chem. 1998; 273: 23629.
Boado, R.J., Li, J.Y., Nagaya, M., Zhang, C., and Pardridge, W.M. Selective expression of the large neutral amino acid transporter at the blood-brain barrier. Proc. Natl. Acad. Sci. USA 1999; 96: 12079.
Smith, Q.R. Transport of glutamate and other amino acids at the blood-brain barrier. J. Nutr. 2000; 130; 1016S.
Shimura, T., Tabata, S., Ohnishi, T., Terasaki, T., and Tsuji, A. Transport mechanism of a new behaviorally highly potent adrenocorticotropic hormone (ACTH) analog, ebiratide, through the blood-brain barrier. J. Pharmacol. Exp. Ther. 1991; 258: 459.
Terasaki, T., Hirai, K., Sato, H., Kang, Y.S., and Tsuji, A. Absorptive-mediated endocytosis of a dynorphin-like analgesic peptide, E-2078 into the blood-brain barrier. J. Pharmacol. Exp. Ther. 1989; 251:351.
Tsuji, A., Terasaki, T., Takabatake, Y., Tenda, Y., Tamai, I., Yamashima, T., Moritani, S., Tsuruo, T., and Yamashita, J. P-Glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells. Lif, Sci. 1992; 51: 1427.
Schinkel, A.H., Smit, J.J.M., van Tellingen, O., Beijnen, J.H., Wagenaar, E., van Deemter, L., Mol, C.A.A.M., van der Valk, M.A., Robanus-Maandag, E.C., to Riele, H.P.J., Berns, A.J.M., and Borst, P. Disruption of the mouse mdrl a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 1994; 77: 491.
Golden, P.L., and Pardridge, W.M. P-Glycoprotein on astrocyte foot processes of unfixed isolated human brain capillaries. Brain Res. 1999; 819: 143.
Schinkel, A.H. P-Glycoprotein, a gatekeeper in the blood-brain barrier. Adv. Drug Deliv. Rev. 1999; 36: 179.
Kusuhara, H., Suzuki, H., Terasaki, T., Kakee, A., Lemaire, M., and Sugiyama, Y. PGlycoprotein mediates the efflux of quinidine across the blood-brain barrier. J. Pharmacol. Exp. Ther. 1997; 283: 574.
Kakee, A., Terasaki, T., and Sugiyama, Y. Brain efflux index as a novel method of analyzing efflux transport at the blood-brain barrier. J. Pharmacol. Exp. Ther. 1996; 277: 1550.
Hosoya, K., Takashima, T., Tetsuka, K., Nagura, T., Ohtsuki, S., Takanaga, H., Ueda, M., Yanai, N., Obinata, M., and Terasaki, T. mRNA expression and transport characterization of conditionally immortalized rat brain capillary endothelial cell lines; a new in vitro BBB model for drug targeting. J. Drug Target. 2000a; 8: 357.
Hosoya, K., Tetsuka, K., Nagase, K., Tomi, M., Saeki, S., Ohtsuki, S., Takanaga, H., Yanai, N., Obinata, M., Kikuchi, A., Okano,T., and Terasaki, T. Conditionally immortalized brain capillary endothelial cell lines established from transgenic mouse harboring temperature-sensitive SV 40 large T-antigen gene. AAPS Pharmsci. 2000b; 2:article 27,(http://www.pharmsci.org/).
Hosoya, K., Sugawara, M., Asaba, H., and Terasaki, T. Blood-brain barrier produces significant efflux of L-aspartic acid but not D-aspartic acid: in vivo evidence using the brain efflux index method. J. Neurochem. 1999; 73: 1206.
Kakee, A., Takanaga, H., Terasaki, T., Naito, M., Tsuruo, T., and Sugiyama Y. Efflux of a suppressive neurotransmitter, GABA, across the blood-brain barrier. J. Neurochem. 2001; 79.• 110.
Asaba, H., Hosoya, K., Takanaga, H., Ohtsuki, S., Tamura, E., Takizawa, T., and Terasaki, T. Blood-brain barrier is involved in the efflux transport of a neuroactive steroid, dehydroepiandrosterone sulfate, via organic anion transporting polypeptide 2. J. Neurochem. 2000; 75:1907.
Hosoya, K., Asaba, H., and Terasaki, T. Brain-to-blood efflux transport of estrone-3sulfate at the blood-brain barrier in rats. Life Sci. 2000c; 67: 2699.
Takanaga, H., Ohtsuki, S., Hosoya, K., and Terasaki, T. GAT2/BGT-1 as a system responsible for the transport of y-aminobutyric acid at the mouse blood-brain barrier. J. Cereb. Blood Flow Metab. 2001; 21: 1232.
Betz, A.L., and Goldstein, G.W. Polarity of the blood-brain barrier: neutral amino acid transport into isolated brain capillaries. Science 1978; 202: 225.
Takanaga, H., Tokuda, N., Ohtsuki, S., Hosoya, K., and Terasaki, T. ATA2 is predominantly expressed as system A at the blood-brain barrier and acts as brain-to-blood efflux transport for L-proline. Mol. Pharmacol. 2002, in press.
Takasawa, K., Terasaki, T., Suzuki, H., and Sugiyama, Y. In vivo evidence for carrier-mediated efflux transport of 3’-azido-3’-deoxythymidine and 2’,3’-dideoxyinosine across the blood-brain barrier via a probenecid-sensitive transport system. J. Pharmacol. Exp. Ther. 1997; 281: 369.
Bodor, N., and Buchwald, P. Recent advances in the brain targeting of neuropharmaceuticals by chemical delivery systems. Adv. Drug Deliv. Rev. 1999; 36: 229.
Pardridge, W.M. Vector-mediated drug delivery to the brain. Adv. Drug Deliv. Rev. 1999; 36: 299.
Shi, N., Zhang, Y., Zhu, C., Boado, R.J., and Pardridge, W.M. Brain-specific expression of an exogenous gene after i.v. administration. Proc. Natl. Acad. Sci. USA 2001; 98: 12754.
Venter, J.C., Adams, M.D., Myers, E.W., et al. The sequence of the human genome. Science 2001; 291: 1304.
Terasaki, T., and Hosoya, K. Conditionally immortalized cell lines as a new in vitro model for the study of barrier functions. Biol. Pharm. Bull. 2001; 24: 111.
Kakee, A., Terasaki, T., and Sugiyama, Y. Selective brain to blood efflux transport of para-aminohippuric acid across the blood-brain barrier: In vivo evidence by use of the Brain Efflux Index method. J. Pharmcol. Exp. Ther. 1997; 283: 1018.
Komura, J., Tamai, I., Senmaru, M., Terasaki, T., Sai, Y., and Tsuji, A. Sodium and chloride ion-dependent transport of beta-alanine across the blood-brain barrier. J. Neurochem. 1996; 67: 330.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2002 Springer Science+Business Media New York
About this chapter
Cite this chapter
Hosoya, Ki., Ohtsuki, S., Terasaki, T. (2002). Blood-Brain Barrier Transport and Drug Targeting to the Brain. In: Muzykantov, V., Torchilin, V. (eds) Biomedical Aspects of Drug Targeting. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-4627-3_16
Download citation
DOI: https://doi.org/10.1007/978-1-4757-4627-3_16
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4419-5312-4
Online ISBN: 978-1-4757-4627-3
eBook Packages: Springer Book Archive