Drug delivery across the blood–brain barrier: why is it difficult? how to measure and improve it?

Bibliography

• REESE TS, FEDER N, BRIGHTMAN MW: Electron microscopic study of the blood-brain and blood-cerebrospinal fluid barriers with microperoxidase. J. Neuropathol. Exp. Neurol. (1971) 30(1):137-138.
   PubMedGoogle Scholar
• REESE TS, KARNOVSKY MJ: Fine structural localization of a blood-brain barrier to exogenous peroxidase. J. Cell Biol. (1967) 34(1):207-217.
   PubMed Web of Science ®Google Scholar
• CORNFORD EM, HYMAN S, CORNFORD ME, LANDAW EM, DELGADO-ESCUETA AV: Interictal seizure resections show two configurations of endothelial Glut1 glucose transporter in the human blood-brain barrier. J. Cereb. Blood Flow Metab. (1998) 18(1):26-42.
   PubMed Web of Science ®Google Scholar
• TAO-CHENG JH, NAGY Z, BRIGHTMAN MW: Tight junctions of brain endothelium in vitro are enhanced by astroglia. J. Neurosci. (1987) 7(10):3293-3299.
   PubMed Web of Science ®Google Scholar
• HURST RD, FRITZ IB: Properties of an immortalised vascular endothelial/glioma cell co-culture model of the blood-brain barrier. J. Cell. Physiol. (1996) 167(1):81-88.
   PubMed Web of Science ®Google Scholar
• SOBUE K, YAMAMOTO N, YONEDA K et al.: Induction of blood-brain barrier properties in immortalized bovine brain endothelial cells by astrocytic factors. Neurosci. Res. (1999) 35(2):155-164.
   PubMed Web of Science ®Google Scholar
• JANZER RC, RAFF MC: Astrocytes induce blood-brain barrier properties in endothelial cells. Nature (1987) 325(6101):253-257.
   PubMed Web of Science ®Google Scholar
• WILLIS CL, LEACH L, CLARKE GJ, NOLAN CC, RAY DE: Reversible disruption of tight junction complexes in the rat blood-brain barrier, following transitory focal astrocyte loss. Glia (2004) 48(1):1-13.
   PubMed Web of Science ®Google Scholar
• GERHARDT H, BETSHOLTZ C: Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res. (2003) 314(1):15-23.
   PubMed Web of Science ®Google Scholar
• BALABANOV R, DORE-DUFFY P: Role of the CNS microvascular pericyte in the blood-brain barrier. J. Neurosci. Res. (1998) 53(6):637-644.
   PubMed Web of Science ®Google Scholar
• BEREZOWSKI V, LANDRY C, DEHOUCK MP, CECCHELLI R, FENART L: Contribution of glial cells and pericytes to the mRNA profiles of P-glycoprotein and multidrug resistance-associated proteins in an in vitro model of the blood-brain barrier. Brain Res. (2004) 1018(1):1-9.
   PubMed Web of Science ®Google Scholar
• TONTSCH U, BAUER HC: Glial cells and neurons induce blood-brain barrier related enzymes in cultured cerebral endothelial cells. Brain Res. (1991) 539(2):247-253.
   PubMed Web of Science ®Google Scholar
• WU D, CLEMENT JG, PARDRIDGE WM: Low blood-brain barrier permeability to azidothymidine (AZT), 3TC, and thymidine in the rat. Brain Res. (1998) 791(1-2):313-316.
   PubMed Web of Science ®Google Scholar
• PARK S, SINKO PJ: P-glycoprotein and mutlidrug resistance-associated proteins limit the brain uptake of saquinavir in mice. J. Pharmacol. Exp. Ther. (2005) 312(3):1249-1256.
   PubMed Web of Science ®Google Scholar
• KANDANEARATCHI A, WILLIAMS B, EVERALL IP: Assessing the efficacy of highly active antiretroviral therapy in the brain. Brain Pathol. (2003) 13(1):104-110.
   PubMed Web of Science ®Google Scholar
• BARTON C: CNS Drug Discoveries: What the Future Holds. Espicom Business Intelligence (2005).
   Google Scholar
• GHOSE AK, VISWANADHAN VN, WENDOLOSKI JJ: A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J. Comb. Chem. (1999) 1(1):55-68.
   PubMed Web of Science ®Google Scholar
• LIPINSKI CA: Drug-like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Toxicol. Methods (2000) 44(1):235-249.
   PubMed Web of Science ®Google Scholar
• VAN DE WATERBEEMD H, CAMENISCH G, FOLKERS G, CHRETIEN JR, RAEVSKY OA: Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors. J. Drug Target. (1998) 6(2):151-165.
   PubMed Web of Science ®Google Scholar
• CLARK DE: Prediction of intestinal absorption and blood-brain barrier penetration by computational methods. Comb. Chem. High Throughput Screen (2001) 4(6):477-496.
   PubMed Web of Science ®Google Scholar
• BASAK SC, GUTE BD, DREWES LR: Predicting blood-brain transport of drugs: a computational approach. Pharm. Res. (1996) 13(5):775-778.
   PubMed Web of Science ®Google Scholar
• FISCHER H, GOTTSCHLICH R, SEELIG A: Blood-brain barrier permeation: molecular parameters governing passive diffusion. J. Membr. Biol. (1998) 165(3):201-211.
   PubMed Web of Science ®Google Scholar
• AJAY, BEMIS GW, MURCKO MA: Designing libraries with CNS activity. J. Med. Chem. (1999) 42(24):4942-4951.
   PubMed Web of Science ®Google Scholar
• ADENOT M, LAHANA R: Blood-brain barrier permeation models: discriminating between potential CNS and non-CNS drugs including P-glycoprotein substrates. J. Chem. Inf. Comput. Sci. (2004) 44(1):239-248.
   PubMedGoogle Scholar
• DEAN M, HAMON Y, CHIMINI G: The human ATP-binding cassette (ABC) transporter superfamily. J. Lipid Res. (2001) 42(7):1007-1017.
   PubMed Web of Science ®Google Scholar
• JONES PM, GEORGE AM: Symmetry and structure in P-glycoprotein and ABC transporters what goes around comes around. Eur. J. Biochem. (2000) 267(17):5298-5305.
   PubMedGoogle Scholar
• ROSENBERG MF, CALLAGHAN R, FORD RC, HIGGINS CF: Structure of the multidrug resistance P-glycoprotein to 2.5 nm resolution determined by electron microscopy and image analysis. J. Biol. Chem. (1997) 272(16):10685-10694.
   PubMed Web of Science ®Google Scholar
• XU J, LIU Y, YANG Y, BATES S, ZHANG JT: Characterization of oligomeric human half-ABC transporter ATP-binding cassette G2. J. Biol. Chem. (2004) 279(19):19781-19789.
   PubMed Web of Science ®Google Scholar
• HENRIKSEN U, GETHER U, LITMAN T: Effect of Walker A mutation (K86M) on oligomerization and surface targeting of the multidrug resistance transporter ABCG2. J. Cell Sci. (2005) 118(7):1417-1426.
   PubMed Web of Science ®Google Scholar
• JULIANO RL, LING V: A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim. Biophys. Acta (1976) 455(1):152-162.
   PubMed Web of Science ®Google Scholar
• PARDRIDGE WM, GOLDEN PL, KANG YS, BICKEL U: Brain microvascular and astrocyte localization of P-glycoprotein. J. Neurochem. (1997) 68(3):1278-1285.
   PubMed Web of Science ®Google Scholar
• CORDON-CARDO C, O’BRIEN JP, CASALS D et al.: Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc. Natl. Acad. Sci. USA (1989) 86(2):695-698.
   PubMed Web of Science ®Google Scholar
• BEAULIEU E, DEMEULE M, GHITESCU L, BELIVEAU R: P-glycoprotein is strongly expressed in the luminal membranes of the endothelium of blood vessels in the brain. Biochem. J. (1997) 326(Pt 2):539-544.
   PubMed Web of Science ®Google Scholar
• VIRGINTINO D, ROBERTSON D, ERREDE M et al.: Expression of P-glycoprotein in human cerebral cortex microvessels. J. Histochem. Cytochem. (2002) 50(12):1671-1676.
   PubMed Web of Science ®Google Scholar
• VOLK HA, BURKHARDT K, POTSCHKA H, CHEN J, BECKER A, LOSCHER W: Neuronal expression of the drug efflux transporter P-glycoprotein in the rat hippocampus after limbic seizures. Neuroscience (2004) 123(3):751-759.
   PubMed Web of Science ®Google Scholar
• VOLK H, POTSCHKA H, LOSCHER W: Immunohistochemical localization of P-glycoprotein in rat brain and detection of its increased expression by seizures are sensitive to fixation and staining variables. J. Histochem. Cytochem. (2005) 53(4):517-531.
   PubMed Web of Science ®Google Scholar
• NIES AT, JEDLITSCHKY G, KONIG J et al.: Expression and immunolocalization of the multidrug resistance proteins, MRP1-MRP6 (ABCC1-ABCC6), in human brain. Neuroscience (2004) 129(2):349-360.
   PubMed Web of Science ®Google Scholar
• COORAY HC, BLACKMORE CG, MASKELL L, BARRAND MA: Localisation of breast cancer resistance protein in microvessel endothelium of human brain. Neuroreport (2002) 13(16):2059-2063.
   PubMed Web of Science ®Google Scholar
• MILLER DS, NOBMANN SN, GUTMANN H, TOEROEK M, DREWE J, FRICKER G: Xenobiotic transport across isolated brain microvessels studied by confocal microscopy. Mol. Pharmacol. (2000) 58(6):1357-1367.
   PubMed Web of Science ®Google Scholar
• ZHANG Y, HAN H, ELMQUIST WF, MILLER DW: Expression of various multidrug resistance-associated protein (MRP) homologues in brain microvessel endothelial cells. Brain Res. (2000) 876(1-2):148-153.
   PubMed Web of Science ®Google Scholar
• DOYLE LA, YANG W, ABRUZZO LV et al.: A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc. Natl. Acad. Sci. USA (1998) 95(26):15665-15670.
   PubMed Web of Science ®Google Scholar
• MIYAKE K, MICKLEY L, LITMAN T et al.: Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: demonstration of homology to abc transport genes. Cancer Res. (1999) 59(1):8-13.
   PubMed Web of Science ®Google Scholar
• ALLIKMETS R, SCHRIML LM, HUTCHINSON A, ROMANO-SPICA V, DEAN M: A human placenta-specific ATP-binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance. Cancer Res. (1998) 58(23):5337-5339.
   PubMed Web of Science ®Google Scholar
• MALIEPAARD M, SCHEFFER GL, FANEYTE IF et al.: Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res. (2001) 61(8):3458-3464.
   PubMed Web of Science ®Google Scholar
• BUNTING KD: ABC transporters as phenotypic markers and functional regulators of stem cells. Stem Cells (2002) 20(1):11-20.
   PubMed Web of Science ®Google Scholar
• GERHART DZ, LEVASSEUR RJ, BRODERIUS MA, DREWES LR: Glucose transporter localization in brain using light and electron immunocytochemistry. J. Neurosci. Res. (1989) 22(4):464-472.
   PubMed Web of Science ®Google Scholar
• KUSUHARA H, SUGIYAMA Y: Active efflux across the blood-brain barrier: role of the solute carrier family. NeuroRx (2005) 2(1):73-85.
   PubMedGoogle Scholar
• KULLAK-UBLICK GA, HAGENBUCH B, STIEGER B et al.: Molecular and functional characterization of an organic anion transporting polypeptide cloned from human liver. Gastroenterology (1995) 109(4):1274-1282.
   PubMed Web of Science ®Google Scholar
• GAO B, HAGENBUCH B, KULLAK-UBLICK GA, BENKE D, AGUZZI A, MEIER PJ: Organic anion-transporting polypeptides mediate transport of opioid peptides across blood-brain barrier. J. Pharmacol. Exp. Ther. (2000) 294(1):73-79.
   PubMed Web of Science ®Google Scholar
• CVETKOVIC M, LEAKE B, FROMM MF, WILKINSON GR, KIM RB: OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab. Dispos. (1999) 27(8):866-871.
   PubMed Web of Science ®Google Scholar
• SU Y, ZHANG X, SINKO PJ: Human organic anion-transporting polypeptide OATP-A (SLC21A3) acts in concert with P-glycoprotein and multidrug resistance protein 2 in the vectorial transport of saquinavir in Hep G2 Cells. Mol. Pharm. (2004) 1(1):49-56.
   PubMed Web of Science ®Google Scholar
• HOSOYAMADA M, SEKINE T, KANAI Y, ENDOU H: Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney. Am. J. Physiol. (1999) 276(1 Pt 2):F122-F128.
   PubMed Web of Science ®Google Scholar
• RACE JE, GRASSL SM, WILLIAMS WJ, HOLTZMAN EJ: Molecular cloning and characterization of two novel human renal organic anion transporters (hOAT1 and hOAT3). Biochem. Biophys. Res. Commun. (1999) 255(2):508-514.
   PubMed Web of Science ®Google Scholar
• CHA SH, SEKINE T, FUKUSHIMA JI et al.: Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol. Pharmacol. (2001) 59(5):1277-1286.
   PubMed Web of Science ®Google Scholar
• KIKUCHI R, KUSUHARA H, SUGIYAMA D, SUGIYAMA Y: Contribution of organic anion transporter 3 (Slc22a8) to the elimination of p-aminohippuric acid and benzylpenicillin across the blood-brain barrier. J. Pharmacol. Exp. Ther. (2003) 306(1):51-58.
   PubMed Web of Science ®Google Scholar
• MORI S, OHTSUKI S, TAKANAGA H, KIKKAWA T, KANG YS, TERASAKI T: Organic anion transporter 3 is involved in the brain-to-blood efflux transport of thiopurine nucleobase analogs. J. Neurochem. (2004) 90(4):931-941.
   PubMed Web of Science ®Google Scholar
• KIKUCHI R, KUSUHARA H, ABE T, ENDOU H, SUGIYAMA Y: Involvement of multiple transporters in the efflux of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors across the blood-brain barrier. J. Pharmacol. Exp. Ther. (2004) 311(3):1147-1153.
   PubMed Web of Science ®Google Scholar
• SHUSTA EV, BOADO RJ, PARDRIDGE WM: Vascular proteomics and subtractive antibody expression cloning. Mol. Cell. Proteomics (2002) 1(1):75-82.
   PubMed Web of Science ®Google Scholar
• PARDRIDGE WM: Blood-brain barrier genomics and the use of endogenous transporters to cause drug penetration into the brain. Curr. Opin. Drug Discov. Devel. (2003) 6(5):683-691.
   PubMed Web of Science ®Google Scholar
• BICKEL U: How to measure drug transport across the blood–brain barrier. NeuroRx (2005) 2(1):15-26.
   PubMedGoogle Scholar
• MURUGANANDAM A, HERX LM, MONETTE R, DURKIN JP, STANIMIROVIC DB: Development of immortalized human cerebromicrovascular endothelial cell line as an in vitro model of the human blood-brain barrier. FASEB J. (1997) 11(13):1187-1197.
   PubMed Web of Science ®Google Scholar
• TATSUTA T, NAITO M, OH-HARA T, SUGAWARA I, TSURUO T: Functional involvement of P-glycoprotein in blood-brain barrier. J. Biol. Chem. (1992) 267(28):20383-20391.
   PubMed Web of Science ®Google Scholar
• GREENWOOD J, PRYCE G, DEVINE L et al.: SV40 large T immortalised cell lines of the rat blood-brain and blood-retinal barriers retain their phenotypic and immunological characteristics. J. Neuroimmunol. (1996) 71(1-2):51-63.
   PubMed Web of Science ®Google Scholar
• KIDO Y, TAMAI I, OKAMOTO M, SUZUKI F, TSUJI A: Functional clarification of MCT1-mediated transport of monocarboxylic acids at the blood-brain barrier using in vitro cultured cells and in vivo BUI studies. Pharm. Res. (2000) 17(1):55-62.
   PubMed Web of Science ®Google Scholar
• FENART L, BUEE-SCHERRER V, DESCAMPS L et al.: Inhibition of P-glycoprotein: rapid assessment of its implication in blood-brain barrier integrity and drug transport to the brain by an in vitro model of the blood-brain barrier. Pharm. Res. (1998) 15(7):993-1000.
   PubMed Web of Science ®Google Scholar
• RIST RJ, ROMERO IA, CHAN MW, COURAUD PO, ROUX F, ABBOTT NJ: F-actin cytoskeleton and sucrose permeability of immortalised rat brain microvascular endothelial cell monolayers: effects of cyclic AMP and astrocytic factors. Brain Res. (1997) 768(1-2):10-18.
   PubMed Web of Science ®Google Scholar
• WOLBURG H, NEUHAUS J, KNIESEL U et al.: Modulation of tight junction structure in blood-brain barrier endothelial cells. Effects of tissue culture, second messengers and cocultured astrocytes. J. Cell Sci. (1994) 107(5):1347-1357.
   PubMed Web of Science ®Google Scholar
• ROUX F, DURIEU-TRAUTMANN O, CHAVEROT N et al.: Regulation of gamma-glutamyl transpeptidase and alkaline phosphatase activities in immortalized rat brain microvessel endothelial cells. J. Cell. Physiol. (1994) 159(1):101-113.
   PubMed Web of Science ®Google Scholar
• RAUH J, MEYER J, BEUCKMANN C, GALLA HJ: Development of an in vitro cell culture system to mimic the blood-brain barrier. Prog. Brain Res. (1992) 91:117-121.
   PubMed Web of Science ®Google Scholar
• O’DONNELL ME, MARTINEZ A, SUN D: Endothelial Na-K-Cl cotransport regulation by tonicity and hormones: phosphorylation of cotransport protein. Am. J. Physiol. Cell Physiol (1995) 269(6):C1513-C1523.
   Web of Science ®Google Scholar
• BOADO RJ, WANG L, PARDRIDGE WM: Enhanced expression of the blood-brain barrier GLUT1 glucose transporter gene by brain-derived factors. Brain Res. Mol. Brain Res. (1994) 22(1-4):259-267.
   PubMedGoogle Scholar
• GAILLARD PJ, VAN DER SANDT IC, VOORWINDEN LH et al.: Astrocytes increase the functional expression of P-glycoprotein in an in vitro model of the blood-brain barrier. Pharm. Res. (2000) 17(10):1198-1205.
   PubMed Web of Science ®Google Scholar
• RUBIN LL, HALL DE, PORTER S et al.: A cell culture model of the blood-brain barrier. J. Cell Biol. (1991) 115(6):1725-1735.
   PubMed Web of Science ®Google Scholar
• EL HAFNY B, BOURRE JM, ROUX F: Synergistic stimulation of gamma-glutamyl transpeptidase and alkaline phosphatase activities by retinoic acid and astroglial factors in immortalized rat brain microvessel endothelial cells. J. Cell. Physiol. (1996) 167(3):451-460.
   PubMed Web of Science ®Google Scholar
• O’DONNELL ME, MARTINEZ A, SUN D: Cerebral microvascular endothelial cell Na-K-Cl cotransport: regulation by astrocyte-conditioned medium. Am. J. Physiol. Cell Physiol (1995) 268(3):C747-C754.
   Web of Science ®Google Scholar
• KIDO Y, TAMAI I, NAKANISHI T et al.: Evaluation of blood-brain barrier transporters by co-culture of brain capillary endothelial cells with astrocytes. Drug Metab. Pharmacokinet. (2002) 17(1):34-41.
   PubMedGoogle Scholar
• KONDO T, KINOUCHI H, KAWASE M, YOSHIMOTO T: Astroglial cells inhibit the increasing permeability of brain endothelial cell monolayer following hypoxia/reoxygenation. Neurosci. Lett. (1996) 208(2):101-104.
   PubMed Web of Science ®Google Scholar
• ISOBE I, WATANABE T, YOTSUYANAGI T et al.: Astrocytic contributions to blood-brain barrier (BBB) formation by endothelial cells: a possible use of aortic endothelial cell for in vitro BBB model. Neurochem. Int. (1996) 28(5-6):523-533.
   PubMed Web of Science ®Google Scholar
• DEHOUCK MP, MERESSE S, DELORME P, FRUCHART JC, CECCHELLI R: An easier, reproducible, and mass-production method to study the blood-brain barrier in vitro. J. Neurochem. (1990) 54(5):1798-1801.
   PubMed Web of Science ®Google Scholar
• GAILLARD PJ, VOORWINDEN LH, NIELSEN JL et al.: Establishment and functional characterization of an in vitro model of the blood-brain barrier, comprising a co-culture of brain capillary endothelial cells and astrocytes. Eur. J. Pharm. Sci. (2001) 12(3):215-222.
   PubMed Web of Science ®Google Scholar
• KONDO T, IMAIZUMI S, KATO I, YOSHIMOTO T: Isolation and culture of brain endothelial cells and establishment of in vitro blood-brain barrier model. Cell Transplant. (1994) 3(Suppl. 1):S35-S37.
   PubMed Web of Science ®Google Scholar
• RAUB TJ, KUENTZEL SL, SAWADA GA: Permeability of bovine brain microvessel endothelial cells in vitro: barrier tightening by a factor released from astroglioma cells. Exp. Cell Res. (1992) 199(2):330-340.
   PubMed Web of Science ®Google Scholar
• DEHOUCK MP, JOLLIET-RIANT P, BREE F, FRUCHART JC, CECCHELLI R, TILLEMENT JP: Drug transfer across the blood-brain barrier: correlation between in vitro and in vivo models. J. Neurochem. (1992) 58(5):1790-1797.
   PubMed Web of Science ®Google Scholar
• LOHMANN C, HUWEL S, GALLA HJ: Predicting blood-brain barrier permeability of drugs: evaluation of different in vitro assays. J. Drug Target. (2002) 10(4):263-276.
   PubMed Web of Science ®Google Scholar
• LUNDQUIST S, RENFTEL M, BRILLAULT J, FENART L, CECCHELLI R, DEHOUCK MP: Prediction of drug transport through the blood-brain barrier in vivo: a comparison between two in vitro cell models. Pharm. Res. (2002) 19(7):976-981.
   PubMed Web of Science ®Google Scholar
• FULLER SD, SIMONS K: Transferrin receptor polarity and recycling accuracy in ‘tight’ and ‘leaky’ strains of Madin-Darby canine kidney cells. J. Cell Biol. (1986) 103(5):1767-1779.
   PubMed Web of Science ®Google Scholar
• VAN MEER G, STELZER EH, WIJNAENDTS-VAN-RESANDT RW, SIMONS K: Sorting of sphingolipids in epithelial (Madin-Darby canine kidney) cells. J. Cell Biol. (1987) 105(4):1623-1635.
   PubMed Web of Science ®Google Scholar
• STEVENSON BR, ANDERSON JM, GOODENOUGH DA, MOOSEKER MS: Tight junction structure and ZO-1 content are identical in two strains of Madin-Darby canine kidney cells which differ in transepithelial resistance. J. Cell Biol. (1988) 107(6 Pt 1):2401-2408.
   PubMed Web of Science ®Google Scholar
• DOAN KM, HUMPHREYS JE, WEBSTER LO et al.: Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J. Pharmacol. Exp. Ther. (2002) 303(3):1029-1037.
   PubMed Web of Science ®Google Scholar
• WANG Q, RAGER JD, WEINSTEIN K et al.: Evaluation of the MDR-MDCK cell line as a permeability screen for the blood-brain barrier. Int. J. Pharm. (2005) 288:349-359.
   Google Scholar
• RICHARDSON JC, SCALERA V, SIMMONS NL: Identification of two strains of MDCK cells which resemble separate nephron tubule segments. Biochim. Biophys. Acta (1981) 673(1):26-36.
   PubMed Web of Science ®Google Scholar
• GUO A, MARINARO W, HU P, SINKO PJ: Delineating the contribution of secretory transporters in the efflux of etoposide using Madin-Darby canine kidney (MDCK) cells overexpressing P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP1), and canalicular multispecific organic anion transporter (cMOAT). Drug Metab. Dispos. (2002) 30(4):457-463.
   PubMed Web of Science ®Google Scholar
• CRONE C, OLESEN SP: Electrical resistance of brain microvascular endothelium. Brain Res. (1982) 241(1):49-55.
   PubMed Web of Science ®Google Scholar
• BUTT AM, JONES HC: Effect of histamine and antagonists on electrical resistance across the blood-brain barrier in rat brain-surface microvessels. Brain Res. (1992) 569(1):100-105.
   PubMed Web of Science ®Google Scholar
• OHNO K, PETTIGREW KD, RAPOPORT SI: Lower limits of cerebrovascular permeability to nonelectrolytes in the conscious rat. Am. J. Physiol. (1978) 235(3):H299-H307.
   PubMed Web of Science ®Google Scholar
• OLDENDORF WH: Measurement of brain uptake of radiolabeled substances using a tritiated water internal standard. Brain Res. (1970) 24(2):372-376.
   PubMedGoogle Scholar
• TAKASATO Y, RAPOPORT SI, SMITH QR: An in situ brain perfusion technique to study cerebrovascular transport in the rat. Am. J. Physiol. (1984) 247(3 Pt 2):H484-H493.
   PubMed Web of Science ®Google Scholar
• DAGENAIS C, ROUSSELLE C, POLLACK GM, SCHERRMANN JM: Development of an in situ mouse brain perfusion model and its application to mdr1a P-glycoprotein-deficient mice. J. Cereb. Blood Flow Metab. (2000) 20(2):381-386.
   PubMed Web of Science ®Google Scholar
• MURAKAMI H, TAKANAGA H, MATSUO H, OHTANI H, SAWADA Y: Comparison of blood-brain barrier permeability in mice and rats using in situ brain perfusion technique. Am. J. Physiol. Heart Circ. Physiol. (2000) 279(3):H1022-H1028.
   PubMed Web of Science ®Google Scholar
• KAKEE A, TERASAKI T, SUGIYAMA Y: Brain efflux index as a novel method of analyzing efflux transport at the blood-brain barrier. J. Pharmacol. Exp. Ther. (1996) 277(3):1550-1559.
   PubMed Web of Science ®Google Scholar
• KUSUHARA H, SUZUKI H, TERASAKI T, KAKEE A, LEMAIRE M, SUGIYAMA Y: P-glycoprotein mediates the efflux of quinidine across the blood-brain barrier. J. Pharmacol. Exp. Ther. (1997) 283(2):574-580.
   PubMed Web of Science ®Google Scholar
• ASABA H, HOSOYA K, TAKANAGA H et al.: 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(5):1907-1916.
   PubMed Web of Science ®Google Scholar
• KAKEE A, TAKANAGA H, TERASAKI T, NAITO M, TSURUO T, SUGIYAMA Y: Efflux of a suppressive neurotransmitter, GABA, across the blood-brain barrier. J. Neurochem. (2001) 79(1):110-118.
   PubMed Web of Science ®Google Scholar
• MORIKI Y, SUZUKI T, FUKAMI T, HANANO M, TOMONO K, WATANABE J: Involvement of P-glycoprotein in blood-brain barrier transport of pentazocine in rats using brain uptake index method. Biol. Pharm. Bull. (2004) 27(6):932-935.
   PubMed Web of Science ®Google Scholar
• RAYBON JJ, BOJE KM: A critical evaluation of the brain efflux index method as applied to the nitric oxide synthase inhibitor, aminoguanidine. Biopharm. Drug Dispos. (2001) 22(9):391-401.
   PubMed Web of Science ®Google Scholar
• KELDER J, GROOTENHUIS PD, BAYADA DM, DELBRESSINE LP, PLOEMEN JP: Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs. Pharm. Res. (1999) 16(10):1514-1519.
   PubMed Web of Science ®Google Scholar
• NEUWELT EA, SPECHT HD, BARNETT PA et al.: Increased delivery of tumor-specific monoclonal antibodies to brain after osmotic blood-brain barrier modification in patients with melanoma metastatic to the central nervous system. Neurosurgery (1987) 20(6):885-895.
   PubMed Web of Science ®Google Scholar
• KREWSON CE, KLARMAN ML, SALTZMAN WM: Distribution of nerve growth factor following direct delivery to brain interstitium. Brain Res. (1995) 680(1-2):196-206.
   PubMed Web of Science ®Google Scholar
• FREY WH, LIU J, CHEN XQ et al.: Delivery of I-125-NGF to the brain via the olfactory route. Drug Deliv. (1997) 4(2):87-92.
   Web of Science ®Google Scholar
• SHIPLEY MT: Transport of molecules from nose to brain: transneuronal anterograde and retrograde labeling in the rat olfactory system by wheat germ agglutinin- horseradish peroxidase applied to the nasal epithelium. Brain Res. Bull. (1985) 15(2):129-142.
   PubMed Web of Science ®Google Scholar
• PARDRIDGE WM: Receptor-mediated peptide transport through the blood-brain barrier. Endocr. Rev. (1986) 7(3):314-330.
   PubMed Web of Science ®Google Scholar
• OLIVIER JC: Drug transport to brain with targeted nanoparticles. NeuroRx (2005) 2(1):108-119.
   PubMedGoogle Scholar
• BEGLEY DJ: ABC transporters and the blood-brain barrier. Curr. Pharm. Des. (2004) 10(12):1295-1312.
   PubMed Web of Science ®Google Scholar
• KIM RB: Drugs as P-glycoprotein substrates, inhibitors, and inducers. Drug Metab. Rev. (2002) 34(1-2):47-54.
   PubMed Web of Science ®Google Scholar
• TSAI TH, LEE CH, YEH PH: Effect of P-glycoprotein modulators on the pharmacokinetics of camptothecin using microdialysis. Br. J. Pharmacol. (2001) 134(6):1245-1252.
   PubMed Web of Science ®Google Scholar
• KEMPER EM, VERHEIJ M, BOOGERD W, BEIJNEN JH, VAN TELLINGEN O: Improved penetration of docetaxel into the brain by co-administration of inhibitors of P-glycoprotein. Eur. J. Cancer (2004) 40(8):1269-1274.
   PubMed Web of Science ®Google Scholar
• KEMPER EM, VAN ZANDBERGEN AE, CLEYPOOL C et al.: Increased penetration of paclitaxel into the brain by inhibition of P-glycoprotein. Clin. Cancer Res. (2003) 9(7):2849-2855.
   PubMed Web of Science ®Google Scholar
• TRAUNECKER HC, STEVENS MC, KERR DJ, FERRY DR: The acridonecarboxamide GF120918 potently reverses P-glycoprotein-mediated resistance in human sarcoma MES-Dx5 cells. Br. J. Cancer (1999) 81(6):942-951.
   PubMed Web of Science ®Google Scholar
• DANTZIG AH, SHEPARD RL, LAW KL et al.: Selectivity of the multidrug resistance modulator, LY335979, for P-glycoprotein and effect on cytochrome P450 activities. J. Pharmacol. Exp. Ther. (1999) 290(2):854-862.
   PubMed Web of Science ®Google Scholar
• MISTRY P, STEWART AJ, DANGERFIELD W et al.: In vitro and in vivo reversal of P-glycoprotein-mediated multidrug resistance by a novel potent modulator, XR9576. Cancer Res. (2001) 61(2):749-758.
   PubMed Web of Science ®Google Scholar
• WANDEL C, KIM RB, KAJIJI S, GUENGERICH P, WILKINSON GR, WOOD AJ: P-glycoprotein and cytochrome P450 3A inhibition: dissociation of inhibitory potencies. Cancer Res. (1999) 59(16):3944-3948.
   PubMed Web of Science ®Google Scholar
• ROWINSKY EK, SMITH L, WANG YM et al.: Phase I and pharmacokinetic study of paclitaxel in combination with biricodar, a novel agent that reverses multidrug resistance conferred by overexpression of both MDR1 and MRP. J. Clin. Oncol. (1998) 16(9):2964-2976.
   PubMed Web of Science ®Google Scholar
• MARTIN C, BERRIDGE G, HIGGINS CF, MISTRY P, CHARLTON P, CALLAGHAN R: Communication between multiple drug binding sites on P-glycoprotein. Mol. Pharmacol. (2000) 58(3):624-632.
   PubMed Web of Science ®Google Scholar
• POLLI JW, JARRETT JL, STUDENBERG SD et al.: Role of P-glycoprotein on the CNS disposition of amprenavir (141W94), an HIV protease inhibitor. Pharm. Res. (1999) 16(8):1206-1212.
   PubMed Web of Science ®Google Scholar
• BREEDVELD P, PLUIM D, CIPRIANI G et al.: The effect of Bcrp1 (Abcg2) on the in vivo pharmacokinetics and brain penetration of imatinib mesylate (Gleevec): implications for the use of breast cancer resistance protein and P-glycoprotein inhibitors to enable the brain penetration of imatinib in patients. Cancer Res. (2005) 65(7):2577-2582.
   PubMed Web of Science ®Google Scholar
• MALIEPAARD M, VAN GASTELEN MA, TOHGO A et al.: Circumvention of breast cancer resistance protein (BCRP)-mediated resistance to camptothecins in vitro using non-substrate drugs or the BCRP inhibitor GF120918. Clin. Cancer Res. (2001) 7(4):935-941.
   PubMed Web of Science ®Google Scholar
• LEE YJ, KUSUHARA H, JONKER JW, SCHINKEL AH, SUGIYAMA Y: Investigation of efflux transport of dehydroepiandrosterone sulfate and mitoxantrone at the mouse blood-brain barrier: a minor role of breast cancer resistance protein. J. Pharmacol. Exp. Ther. (2005) 312(1):44-52.
   PubMed Web of Science ®Google Scholar
• ADVANI R, FISHER GA, LUM BL et al.: A Phase I trial of doxorubicin, paclitaxel, and valspodar (PSC 833), a modulator of multidrug resistance. Clin. Cancer Res. (2001) 7(5):1221-1229.
   PubMed Web of Science ®Google Scholar
• BAUER KS, KARP JE, GARIMELLA TS, WU S, TAN M, ROSS DD: A Phase I and pharmacologic study of idarubicin, cytarabine, etoposide, and the multidrug resistance protein (MDR1/Pgp) inhibitor PSC-833 in patients with refractory leukemia. Leuk. Res. (2005) 29(3):263-271.
   PubMed Web of Science ®Google Scholar
• GREENBERG PL, LEE SJ, ADVANI R et al.: Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a Phase III trial (E2995). J. Clin. Oncol. (2004) 22(6):1078-1086.
   PubMed Web of Science ®Google Scholar
• SASONGKO L, LINK JM, MUZI M et al.: Imaging P-glycoprotein transport activity at the human blood-brain barrier with positron emission tomography. Clin. Pharmacol. Ther. (2005) 77(6):503-514.
   PubMed Web of Science ®Google Scholar
• PLANTING AS, SONNEVELD P, VAN DER GAAST A et al.: A Phase I and pharmacologic study of the MDR converter GF120918 in combination with doxorubicin in patients with advanced solid tumors. Cancer Chemother. Pharmacol. (2005) 55(1):91-99.
   PubMed Web of Science ®Google Scholar
• MCALLISTER MS, KRIZANAC-BENGEZ L, MACCHIA F et al.: Mechanisms of glucose transport at the blood-brain barrier: an in vitro study. Brain Res. (2001) 904(1):20-30.
   PubMed Web of Science ®Google Scholar
• HALESTRAP AP, PRICE NT: The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem. J. (1999) 343(Pt 2):281-299.
   PubMed Web of Science ®Google Scholar
• BOADO RJ, LI JY, NAGAYA M, ZHANG C, PARDRIDGE WM: Selective expression of the large neutral amino acid transporter at the blood–brain barrier. Proc. Natl. Acad. Sci. USA (1999) 96(21):12079-12084.
   PubMed Web of Science ®Google Scholar
• ALLEN DD, SMITH QR: Characterization of the blood-brain barrier choline transporter using the in situ rat brain perfusion technique. J. Neurochem. (2001) 76(4):1032-1041.
   PubMed Web of Science ®Google Scholar
• KING GL, JOHNSON SM: Receptor-mediated transport of insulin across endothelial cells. Science (1985) 227(4694):1583-1586.
   PubMed Web of Science ®Google Scholar
• PARDRIDGE WM, EISENBERG J, YANG J: Human blood-brain barrier insulin receptor. J. Neurochem. (1985) 44(6):1771-1778.
   PubMed Web of Science ®Google Scholar
• PARDRIDGE WM, EISENBERG J, YANG J: Human blood-brain barrier transferrin receptor. Metabolism (1987) 36(9):892-895.
   PubMed Web of Science ®Google Scholar
• GOLDEN PL, MACCAGNAN TJ, PARDRIDGE WM: Human blood-brain barrier leptin receptor. Binding and endocytosis in isolated human brain microvessels. J. Clin. Invest. (1997) 99(1):14-18.
   PubMed Web of Science ®Google Scholar
• HUWYLER J, WU D, PARDRIDGE WM: Brain drug delivery of small molecules using immunoliposomes. Proc. Natl. Acad. Sci. USA (1996) 93(24):14164-14169.
   PubMed Web of Science ®Google Scholar
• PARDRIDGE WM: Tyrosine hydroxylase replacement in experimental Parkinson’s disease with transvascular gene therapy. NeuroRx (2005) 2(1):129-138.
   PubMedGoogle Scholar
• PARDRIDGE WM: Drug and gene targeting to the brain with molecular Trojan horses. Nat. Rev. Drug Discov. (2002) 1(2):131-139.
   PubMed Web of Science ®Google Scholar
• KREUTER J, ALYAUTDIN RN, KHARKEVICH DA, IVANOV AA: Passage of peptides through the blood-brain barrier with colloidal polymer particles (nanoparticles). Brain Res. (1995) 674(1):171-174.
   PubMed Web of Science ®Google Scholar
• KREUTER J: Nanoparticulate systems for brain delivery of drugs. Adv. Drug Deliv. Rev. (2001) 47(1):65-81.
   PubMed Web of Science ®Google Scholar
• OLIVIER JC, HUERTAS R, LEE HJ, CALON F, PARDRIDGE WM: Synthesis of pegylated immunonanoparticles. Pharm. Res. (2002) 19(8):1137-1143.
   PubMed Web of Science ®Google Scholar
• ZHANG Y, PARDRIDGE WM: Delivery of β-galactosidase to mouse brain via the blood–brain barrier transferrin receptor. J. Pharmacol. Exp. Ther. (2005) 313(3):1075-1081.
   PubMed Web of Science ®Google Scholar
• HUWYLER J, YANG J, PARDRIDGE WM: Receptor mediated delivery of daunomycin using immunoliposomes: pharmacokinetics and tissue distribution in the rat. J. Pharmacol. Exp. Ther. (1997) 282(3):1541-1546.
   PubMed Web of Science ®Google Scholar
• DIETZ GP, BAHR M: Delivery of bioactive molecules into the cell: the Trojan horse approach. Mol. Cell. Neurosci. (2004) 27(2):85-131.
   PubMed Web of Science ®Google Scholar
• ZHANG X, WAN L, POOYAN S et al.: Quantitative assessment of the cell penetrating properties of RI-Tat-9: evidence for a cell type-specific barrier at the plasma membrane of epithelial cells. Mol. Pharm. (2004) 1(2):145-155.
   PubMedGoogle Scholar
• ROUSSELLE C, SMIRNOVA M, CLAIR P et al.: Enhanced delivery of doxorubicin into the brain via a peptide-vector-mediated strategy: saturation kinetics and specificity. J. Pharmacol. Exp. Ther. (2001) 296(1):124-131.
   PubMed Web of Science ®Google Scholar
• MAZEL M, CLAIR P, ROUSSELLE C et al.: Doxorubicin-peptide conjugates overcome multidrug resistance. Anticancer Drugs (2001) 12(2):107-116.
   PubMed Web of Science ®Google Scholar
• ROUSSELLE C, CLAIR P, LEFAUCONNIER JM, KACZOREK M, SCHERRMANN JM, TEMSAMANI J: New advances in the transport of doxorubicin through the blood-brain barrier by a peptide vector-mediated strategy. Mol. Pharmacol. (2000) 57(4):679-686.
   PubMed Web of Science ®Google Scholar
• CAO G, PEI W, GE H et al.: In vivo delivery of a Bcl-xL fusion protein containing the TAT protein transduction domain protects against ischemic brain injury and neuronal apoptosis. J. Neurosci. (2002) 22(13):5423-5431.
   PubMed Web of Science ®Google Scholar
• KILIC U, KILIC E, DIETZ GP, BAHR M: Intravenous TAT-GDNF is protective after focal cerebral ischemia in mice. Stroke (2003) 34(5):1304-1310.
   PubMed Web of Science ®Google Scholar
• SCHWARZE SR, HO A, VOCERO-AKBANI A, DOWDY SF: In vivo protein transduction: delivery of a biologically active protein into the mouse. Science (1999) 285(5433):1569-1572.
   PubMed Web of Science ®Google Scholar
• MILLER G: Drug targeting. Breaking down barriers. Science (2002) 297(5584):1116-1118.
   PubMed Web of Science ®Google Scholar