Prodrugs and endogenous transporters: Are they suitable tools for drug targeting into the central nervous system?

Current Pharmaceutical Design

Volumn 17, Issue 32, 2011, Pages 3560-3576

  Pavan, Barbara ^a   Dalpiaz, Alessandro ^a  

^a UNIVERSITY OF FERRARA   (Italy)

Author keywords

AET systems; CMT systems; Endogenous transporters; Lipidization; Prodrug; RMT systems

Indexed keywords

1,3 DIACETYL 2 KETOPROFEN GLYCERIDE; 6 BROMO ASCORBATE; 7 CHLOROKYNURENIC ACID; ACETORPHAN; ACETYL THIORPHAN; ASCORBIC ACID; ASTEMIZOLE; CODEINE; DIAMORPHINE; DICLOFENAMIC ACID; DIPHENHYDRAMINE; DOPAMINE; DOXORUBICIN; FOSCARNET; GLUCOSE; KETOPROFEN; KYNURENIC ACID; L 4 CHLOROKYNUREINE; LEVODOPA; MEPYRAMINE; MORPHINE; NIPECOTIC ACID; OXYBATE SODIUM; PROBENECID; PRODRUG; TERFENADINE; THIORPHAN; TYROSINE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VALPROIC ACID;

ACTIVE TRANSPORT; AREA UNDER THE CURVE; ARTICLE; BLOOD BRAIN BARRIER; CENTRAL NERVOUS SYSTEM; CHEMICAL MODIFICATION; DRUG BLOOD LEVEL; DRUG CONJUGATION; DRUG EFFICACY; DRUG TARGETING; DRUG TRANSPORT; EPITHELIUM CELL; HUMAN; IN VITRO STUDY; IN VIVO STUDY; LIPID SOLUBILITY; NEUROPROTECTION; NONHUMAN; PERMEABILITY BARRIER; PIGMENT EPITHELIUM; PRIORITY JOURNAL;

EID: 82055206096     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/138161211798194486     Document Type: Article

References (156)

1. Begley DJ. Understanding and circumventing the blood-brain barrier. Acta Paediatr Suppl 2003; 443: 83-91.
2. Begley DJ. Delivery of therapeutic agents to the central nervous system: the problems and the possibilities. Pharmacol Ther 2004; 104: 29-45.
3. Pavan B, Dalpiaz A, Ciliberti N, Biondi C, Manfredini S, Vertuani S. Progress in drug delivery to the central nervous system by the prodrug approach. Molecules 2008; 13: 1035-65.
4. Banks WA. Characteristics of compounds that cross the bloodbrain barrier. BMC Neurol 2009; 9(Suppl 1): S3
5. Engelhardt B. The blood-central nervous system barriers actively control immune cell entry into the central nervous system. Curr Pharm Des 2008; 14: 1555-65.
6. Tamai I, Tsuji A. Transporter-Mediated Permeation of Drugs Across the Blood-Brain Barrier. J Pharm Sci 2000; 89: 1371-88.
7. Cohen-Kashi Malina K, Cooper I, Teichberg VI. Closing the gap between the in-vivo and in-vitro blood-brain barrier tightness. Brain Res 2009; 1284: 12-21.
8. Levin V A. Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J Med Chem 1980; 23: 682-4.
9. Choi YK, Kim KW. Blood-neural barrier: its diversity and coordinated cell-to-cell communication. BMB reports 2008; 41: 345-52.
10. Johanson CE, Duncan JA, Stopa EG, Baird A. Enhanced prospects for drug delivery and brain targeting by the choroid plexus-CSF route. Pharm Res 2005; 22: 1011-37.
11. Ghersi-Egea J, Leninger-Muller B, Suleman G, Siest G, Minn A. Localisation of drug-metabolizing enzyme activities to blood-brain interfaces and circumventricular organs. J Neurochem 1994; 62: 1089-96
12. Lindvall M, Hardebo J, Owman C. Barrier mechanisms for neutrotransmitter monoamines in the choroid plexus. Acta Physiol Scand 1980; 108: 215-21.
13. Ghersi-Egea J, Strazielle N, Murat A, Jouvet A, Buénerd A, Belin M. Brain protection at the blood-cerebrospinal fluid interface involves a glutathione- dependent metabolic barrier mechanism. J Cereb Blood Flow Metab 2006; 26: 1165-75.
14. Bauer B, Hartz A, Lucking J, Yang X, Pollack G, Miller D. Coordinated nuclear receptor regulation of the efflux transporter, Mrp2, and the phase-II metabolizing enzyme, GSTpi, at the blood-brain barrier. J Cereb Blood Flow Metab 2008; 28: 1222-34.
15. Sura P, Sura R, Enayet-aletal/et-allah A, Grant D. Distribution and expression of soluble epoxide hydrolase in human brain. J Histochem Cytochem 2008; 56: 551-9.
16. Eyal S, Hsiao P, Unadkay D. Drug Interactions at the blood-brain barrier: Fact or fantasy? Pharmacol Ther 2009; 123: 80-104.
17. Minn A, El-Bacha RDS, Bayol-Denizot C, Lagrange P, Suleman FG. In Begley DJ,. Bradbury M W, Kreuter J, Eds. The bloodbrain barrier and drug delivery to the CNS. New York: Dekker 2000; pp. 145-70.
18. Pardridge W M. The Blood-Brain Barrier: Bottleneck in Brain Drug Development. NeuroRx 2005; 2: 3-14.
19. Pardridge W M. Blood-brain barrier delivery. Drug Discov Today 2007; 12: 54-61.
20. Cunha-Vaz J, Bernardes R, Lobo C. Blood-retinal barrier. Eur J Ophthalmol 2010; 21(Suppl 6): 3-9.
21. Toimela T, Maenpaa H, Mannerstrom M, Tahti H. Development of an in vitro blood-brain barrier model-cytotoxicity of mercury and aluminium. Toxicol Appl Pharmacol 2004; 195: 73-82.
22. Dalpiaz A, Pavan B, Vertuani S, et al. Ascorbic and 6-Br-ascorbic acid conjugates as a tool to increase the therapurtic effects of potentially central active drugs. Eur J Pharm Sci 2005; 24: 259-69.
23. Dalpiaz A, Filosa R, de Caprariis P, et al. Molecular mechanism involved in the transport of a prodrug dopamine glycosyl conjugate. Int J Pharm 2007; 336: 133-9.
24. Garcia-Garcia E, Andrieux K, Gil S, Couvreur P. Colloidal carriers and blood-brain barrier (BBB) translocation: A way to deliver drugs to the brain? Int J Pharmaceut 2005; 298: 274-92.
25. Prokai-Tatrai K, Prokai L. Modifying peptide properties by prodrug design for enhanced transport into the CNS. Prog Drug Res 2003; 61: 155-88.
26. Fischer H, Gottschlich R, Seelig A. Blood-brain barrier permeation: molecular parameters governing passive diffusion. J Membr Biol 1998; 165: 201-11.
27. Trauble H. The movement of molecules across lipid membranes: a molecular theory. J Membr Biol 1971; 4: 193-208.
28. Marrink SJ, Jahnig F, Berendsen HJC. Proton transport across transient single-file water pores in a lipid membrane studied by molecular dynamics simulations. Biophys J 1996; 71: 632-47.
29. Trauble H. The movement of molecules across lipid membranes: a molecular theory. J Membr Biol 1971; 4: 193-208.
30. Marrink SJ, Jahnig F, Berendsen HJC. Proton transport across transient single-file water pores in a lipid membrane studied by molecular dynamics simulations. Biophys J 1996; 71: 632-47.
31. Diamond JM, Wright EM. Molecular forces governing nonelectrolyte permeation through cell membranes. Proc R Soc Lond B Biol Sci 1969; 171: 273-16.
32. Greig NH, Daly EM, Sweeney DJ, Rapoport SI. Pharmacokinetics of chlorambuciltertiary butyl ester, a lipophilic chrambucil derivative that achieves and maintains high concentrations in brain. Cancer Chemother Pharmacol 1990; 25: 320-5.
33. Oldendorf WH. Measurement of brain uptake of radiolabeled substances using a tritiated water internal standard. Brain Res 1970; 24: 372-6.
34. Oldendorf WH, Human S, Braun L, Oldendorf SZ. Blood-brain barrier penetration of morphine, codeine, heroin, and methadone after carotid injection. Science 1972; 178: 984-6.
35. Roques BP, Lucas-Soroca E, Chaillet P, Costentin J, Fournie- Zaluski MC. The enkephalinase inhibitor thiorphan shows antinociceptine activity in mice. Nature 1980; 288: 286-8.
36. Fournie-Zaluski MC, Coric P, Turcaud S, et al. "Mixed inhibitorprodrug" as a new approach toward systemically active inhibitors of enkephalin-degrading enzymes. J Med Chem 1992; 35: 2473-81.
37. Lecomte JM, Costentin J, Vlaiculescu A, et al. Pharmacological properties of acetorphan, a parentererally active "enkephalinase" inhibitor. J Pharmacol Exp Ther 1986; 237: 937-44.
38. Lambert SM, Mergen F, Poupaert JH, Dumont P. Analgesic potency of S-acethylthiorphan after intravenous administration to mice. Eur J Pharmacol 1993; 243: 129-34.
39. Omar FA, Farag H, Bodor N. Synthesis and evaluation of a redox chemical delivery system for brain-enhanced dopamine containing an activated carbamate-type ester. J Drug Target 1994; 2: 309-16.
40. Carelli V, Liberatore F, Scipione L, et al. New systems for the specific delivery and sustained release of dopamine to the brain. J Control Rel 1996, 42: 209-16.
41. Yoshiharu D, Hideki H, Shinobu F, et al. Improved brain delivery of a nonsteroidal anti-inflammatory drug with a synthetic glyceride ester: a preliminary attempt at a CNS drug delivery system for therapy of Alzheimer's disease. J. Drug Target 2000; 8: 371-81.
42. Ohtsuki S, Asaba H, Takanaga H, et al. Role of blood-brain barrier organic anion transporter 3 (OAT3) in the efflux of indoxyl sulfate, a uremic toxin: its involvement in neurotransmitter metabolite clearance from the brain. J Neurochem 2002; 83: 57-66.
43. Akanuma S, Hosoya K, Ito S, Tachikawa M, Terasaki T, Ohtsuki S. Involvement of multidrug resistance-associated protein 4 in efflux transport of prostaglandin E(2) across mouse blood-brain barrier and its inhibition by intravenous administration of cephalosporins. J Pharmacol Exp Ther 2010; 333: 912-9.
44. Loscher W, Potschka H. Blood-Brain Barrier Active Efflux Transporters: ATP-Binding Cassette Gene Family NeuroRX 2005; 2: 86-98.
45. Pardridge WM. Drug Targeting to the Brain. Pharm Res 2007; 24: 1733-44.
46. Patel MM, Goyal BR, Bhadada SV, Bhatt JS, Amin AF. Getting into the brain. CNS Drugs 2009; 23: 35-58.
47. de Boer AG, van der Sandt ICJ, Gaillard PG. The role of drug transporters at the blood brain barrier. Annu Rev Toxicol 2003; 43: 629-56.
48. Oldendorf W H. Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection. Am J Physiol 1971; 221: 1629-39
49. Pardridge WM. Brain metabolism: a perspective from the bloodbrain barrier. Physiol Rev 1983; 63: 1481-535.
50. Rice ME Ascorbate regulation and its neuroprotective role in the brain. Trends Neurosci 2000; 23: 209-16.
51. Kanai Y, Segawa H, Miyamoto K, Uchino H, Takeda E, 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: 23629-32.
52. +) of the rat blood-brain barrier. J Neurochem 1993; 60: 1956-9.
53. Uchino H, Kanai Y, Kim D, et al. Transport of amino acid-related compounds mediated by L-type amino acid transporter 1 (LAT1): insights into the mechanisms of substrate recognition. Mol Pharmacol 2002; 61: 729-37.
54. Verrey F. System L: heteromeric exchangers of large, neutral amino acids involved in directional tranport. Pflugers Arch 2003; 445: 529-33.
55. Tsuji A. Small molecular drug transfer across the blood-brain barrier via carrier-mediated transport systems. NeuroRx 2005; 2: 54-62.
56. Pardridge WM, Boado R.J, Farrell CR. Brain-type glucose transporter (GLUT 1) is selectively localized to the blood-brain barrier. Studies with quantitative western blotting and in situ hybridisation. J Biol Chem 1990; 265: 18035-40.
57. Pardridge WM, Olendorf WH. Kinetics of blood-brain barrier transport of hexoses. Biochim Biophys Acta 1975; 382: 377-92.
58. Mueckler M, Makepeace C. Transmembrane segment 6 of the Glut1 glucose transporter is an outer helix and contains amino acid side chains essential for transport activity. J Biol Chem 2008; 283: 11550-5.
59. Gynther M, Ropponen J, Laine K, et al. Glucose promoiety enables glucose transporter mediated brain uptake of ketoprofen and indomethacin prodrugs in rats. J Med Chem 2009; 52: 3348-53.
60. Griffiths M, Beaumont N, Yao SY, et al. Cloning of a human nucleoside transporter implicated in the cellular uptake of adenosine and chemotherapeutic drugs. Nat Med 1997; 3: 25-6.
61. Griffiths M, Yao SY, Abidi F, et al. Molecular cloning and characterization of a nitrobenzylthioinosineinsensitive (ei) equilibrative nucleoside transporter from human placenta. Biochem J 1997; 328: 739-43.
62. Ritzel MW, Yao SY, Ng AM, Mackey JR, Cass CE, Young JD. Molecular cloning, functional expression and chromosomal localization of a cDNA encoding a human Naƥ/nucleoside cotransporter (hCNT2) selective for purine nucleosides and uridine. Mol Membr Biol 1998; 15: 203-11.
63. Ritzel MW, Yao SY, Huang MY, Elliott JF, Cass CE, Young JD. Molecular cloning and functional expression of cDNAs encoding a human Na??nucleoside cotransporter (hCNT1). Am J Physiol 1997; 272: C707-C14.
64. Ritzel MW, Ng AM, Yao SY, et al. Molecular identification and characterization of novel human and mouse concentrative Naƥ- nucleoside cotransporter proteins (hCNT3 and mCNT3) broadly selective for purine and pyrimidine nucleosides. J Biol Chem 2001; 276: 2914-27.
65. Baldwin SA, Yao SY, Hyde RJ, et al. Functional characterization of novel human and mouse equilibrative nucleoside transporters (hENT3 and mENT3) located in intracellular membranes. J Biol Chem 2005; 280: 15880-7.
66. King AE, Ackley MA, Cass CE, Young JD, Baldwin SA. Nucleoside transporters: From scavengers to novel therapeutic targets. Trends Pharmacol Sci 2006; 27: 416-25.
67. Cornford EM, Oldendorf WH. Independent blood-brain barrier transport systems for nucleic acid precursors. Biochim Biophys Acta 1975; 394: 211-9.
68. Pardridge W M, Yoshikawa T, Kang YS, Miller LP. Blood-brain barrier transport and brain metabolism of adenosine and adenosine analogs. J Pharmacol Exp Ther 1994; 268: 14-8.
69. Chishty M, Begley D J, Abbott N J, Reichel A. Interaction of nucleoside analogues with nucleoside transporters in rat brain endothelial cells. J Drug Targ 2004; 12: 265-72.
70. Gerhart DZ, Enerson BE, Zhdankina OY, Leino RL, Drewes LR. Expression of monocarboxylate transporter MCT1 by brain endothelium and glia in adult and suckling rats. Am J Physiol 1997; 273: E207-13.
71. Urquhart BL, Kim RB. Blood-brain barrier transporters and response to CNS-active drugs. Eur J Clin Pharmacol 2009; 65: 1063-70.
72. Bhattacharya I, Boje KM. GHB (gamma-hydroxybutyrate) carriermediated transport across the blood-brain barrier. J Pharmacol Exp Ther 2004; 311: 92-8.
73. Tamai I, Sai Y, Ono A, et al. Immunohistochemical and functional characterization of pH-dependent intestinal absorption of organic weak acids by monocarboxylic acid transporter MCT1. J Pharm Pharmacol 1999; 51: 1113-21.
74. +-dependent L-ascorbic acid transporters. Nature 1999; 399: 70-5.
75. Durawala R, Song J, Koh W.S, Rumsey SC, Levine M. Cloning and functional characterization of the human sodium-dependent Vitamin C transporters hSVCT1 and hSVCT2. FEBS Lett 1999; 460: 480-4.
76. Rajan DP, Huang W, Dutta B, et al. Human placental sodiumdependent vitamin C transporter (SVCT2): molecular cloning andtransport function. Biochem Biophis Res Comm 1999; 262: 762-8.
77. Sotiriou S, Gispert S, Cheng J, et al. Acorbic acid transporter Slc23a1 is essential for Vitamin C transport into the brain and forperinatal survival. Nature Med 2002; 8, 514-7.
78. Gilchrest B. Anti-sushine Vitamin A. Nature Med 1999; 5: 376-7.
79. Friedman PA, Ziedel ML. Victory at C. Nature Med 1999; 5: 620-1.
80. Rice M.E. Ascorbate regulation and its neuroprotective role in the brain. Trends Neurosci 2000; 23: 209-16.
81. Angelow S, Haselbach M, Galla HJ. Functional characterisation of the active ascorbic acid transport into cerebrospinal fluid using primary cultured choroids plexus cells. Brain Res 2003; 988: 105-13.
82. Hakvoort A, Haselbach M, Galla H J. Active transport properties of porcine choroid plexus cells in culture. Brain Res 1998; 795: 247-56.
83. Nishikimi M, Fukuyama R, Minoshima S, Shimizu M, Yaghi K. Cloning and chromosomal mapping of the human non functional gene for L-gulono-γ-lactone oxidase, the enzyme for L-ascorbic acid biosynthesis missing in man. J Biol Chem 1994; 269: 23215-22.
84. Rose RC, Bode AM. Ocular ascorbate transport and metabolism. Comp Biochem Physiol 1991; 100: 273-85.
85. Manfredini S, Pavan, B, Vertuani S, et al. Design, synthesis and activity of ascorbic acid prodrugs of nipecotic, kynurenic and diclophenamic acids, liable to increase neurotropic activity. J Med Chem 2002; 45: 559-62.
86. Djaletti R, Melamed E. New therapies for Parkinson's disease. J Neurol 2001; 248: 357-62.
87. Leeson PD, Iversen LL. The glycine site on the NMDA receptor: structure-activity relationships and therapeutic potential. J Med Chem 1994; 37: 4053-67.
88. Hokari M, Wu HQ, Schwarcz R, Smith QR. Facilitated brain uptake of 4-chlorokynureine and conversion to 7-chlorokynurenic acid. Neuropharmacol Neurotoxicol 1996; 8: 15-8.
89. Krogsgaard-Larsen P, Johnston GAR. Inhibition of GABA uptake in rat brain slices by nipecotic acid, various isoxazoles and related compounds. J Neurochem 1975; 25, 797-802.
90. Horton RW, Collins JF, Anlezark GM, Melbrum BS. Convulsant and anticonvulsant actions in DBA/2 mice of compounds blocking the reuptake of GABA. Eur J Pharmacol 1979; 59: 75-83.
91. Bonina FP, Arenare L, Palagiano F, et al. Synthesis, stability and pharmacological evaluation of nipecotic acid prodrugs. J Pharm Sci 1999; 88: 561-7.
92. Oberg B. Antiviral effects of phsphonoformate (PFA, foscarnet sodium). Pharmacol Ther 1989; 40: 213-85.
93. Walker I, Nicholls D, Irwin WJ, Freeman S. Drug delivery via active transport at the bloodbrain barrier: affinity of a prodrug of phosphonoformate for the large aminoacid transporter. Int J Pharm 1994; 104: 157-67.
94. Gynther M, Laine K, Ropponen J, et al. Large neutral amino acid transporter enables brain drug delivery via prodrugs. J Med Chem 2008; 51: 932-6.
95. Bilsky E, Egleton RD, Mitchell SA, et al. Enkephalin glycopeptide analogues produce analgesia with reduced dependence liability. J Med Chem 2000; 43: 2586-90.
96. Polt R, Porreca F, Szabo LZ, et al. Proc Natl Acad Sci USA 1994; 91: 7114-8.
97. Elmagbari NO, Egleton RD, Palian MM, et al. Antinociceptive structure-activity studies with enkephalin based oppioid glycopeptides. J Pharmacol Exp Ther 2004; 311: 290-7.
98. Battaglia G, La Russa M, Bruno V, et al. Systematically administered D-glucose conjugates of 7-chlorokynurenic acid are centrally available and exert anticonvulsant activity in rodents. Brain Res. 2000; 860: 149-56.
99. Bonina F, Arenare L, Ippolito R, et al. Synthesis, pharmacokinetics and anticonvulsant activity of 7-chlorokynurenic acid prodrugs. Int J Pharm 2000; 202: 79-88.
100. Fuglang M, Lomholt M, Gjedde A. Blood-brain transfer of glucose and glucose analogues in newborn rats. J Neurochem 1986; 46: 1417-28.
101. Gynther M, Ropponen J, Laine K, et al. Glucose promoiety enables glucose transporter mediated brain uptake of ketoprofen and indomethacin prodrugs in rats. J Med Chem 2009; 52: 3348-53.
102. Lambert DM. Rationale and applications of lipids as prodrug carriers. Eur J Pharm Sci 2000; 2: S15-27.
103. Hodgkins PS, Schwarcz R. Metabolic control of kynurenic acid formation in the rat brain. Dev Neurosci 1998; 20: 408-16.
104. Smith QR. Transport of glutamate and other amino acids at the blood-brain barrier. J Nutr 2000; 130: 1016S-22S.
105. Hull M, Lieb K, Fiebich, BL. Antiinflammatory drugs: a hope for Alzheimer's disease? Expert Opin Invest Drugs 2000; 9: 671-83.
106. Baures PW, Oza V B, Peterson SA, Kelly JW. Synthesis and evaluation of inhibitors of transthyretin amyloid formation based on the nonsteroidal antiinflammatory drug,flufenamic acid. Bioorg Med Chem 1999, 7: 1339-47.
107. Patel PM, Drummond JC, Sano T, Cole DJ, Kalkman CJ, Yaksh TL. Effect of ibuprofen on regional eicosanoid production and neuronal injury after forebrain ischemia in rats.Brain Res. 1993; 614: 315-24.
108. Rumsey SC, Welch RW, Garraffo H M, et al. Specificity of ascorbate analogues for ascorbate transport. Synthesis and detection of [125I]6-deoxy-6-iodo-L-ascorbic acid and characterization of its ascorbate-specific transport properties. J Biol Chem 1999; 274: 23215-22.
109. Dalpiaz A, Pavan B, Scaglianti M, et al. Transporter-mediated effects of diclofenamic acid and its ascorbyl pro-drug in the in vivo neurotropic activity as ascorbyl nipecotic acid coniugate. J Pharm Sci 2004; 93: 78-84.
110. Dalpiaz A, Pavan B, Scaglianti M, et al. Vitamin C and 6-aminovitamin C conjugates of diclofenac: synthesis and evaluation. Int J Pharm 2005; 291: 171-81.
111. Salmaso S, Pappalardo JS, Sawant RR, et al. Targeting glioma cells in vitro with ascorbate-conjugated pharmaceutical nanocarriers. Bioconjugate Chem 2009; 20: 2348-55.
112. Schinkel AH, Smit JJM, van Telligen O, et al. Disruption of mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 1994; 77: 491-502.
113. Schinkel AH. P-Glycoprotein, a gatekeeper in the blood-brain barrier. Adv Drug Delivery Rev 1999; 36: 179-94.
114. Schinkel AH, Wagenaar E, van Deemter L, Mol CAAM, Borst P. Absence of the mdr1a Pglycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin and cyclosporin A. J Clin Invest 1995; 96: 1698-705.
115. de Lange ECM, de Bock G, Schinkel AH, de Boer AG, Breimer DD. BBB transport and P-glycoprotein functionality using mdr1a(-/-) and wild-type mice. Total brain versus microdialysis concentration profiles of rhodamine-123. Pharm Res 1998; 15: 1657-65.
116. Yokogawa K, Takahashi M, Tamai I, et al. Glycoprotein-dependent disposition kinetics of tacrolimus: Studies in mdr1a knockout mice. Pharm Res 1999; 16: 1213-8.
117. Schinkel AH, Jonker JW. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv Drug Deliv Rev 2003; 55: 3-29.
118. Juliano RL, Ling V. A surface glicoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 1976; 455: 152-62.
119. Kartner R., Shales M, Riordan JR, Ling V. Daunorubicin-resistant Chinese hamster ovary cell expressing multidrug resistance and a cell surface P-glicoprotein. Cancer Res 1983; 43: 4413-9.
120. Sun H, Dai H, Shaik N, Elmquist F. Drug efflux transporters in the CNS. Adv Drug Del Rev 2003; 55: 83-105
121. Beaulieu E, Demeule L, Ghiteseu 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: 539-44.
122. Rao VV, Dahlheimer JL, Bardgett ME, et al. Choroid plexus epithelia expression of MDR1 p glycoprotein and multidrug resistance- associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier. Proc Natl Acad Sci USA 1999; 96: 3900-5.
123. Pallis M, Turzanski J, Higashi Y, Russell N. P-glycoprotein in acute myeloid leukaemia: therapeutic implications of its association with both a multidrug-resistant and an apoptosis-resistant phenotype. Leuk Lymphoma 2002; 43: 1221-8.
124. Gennuso F, Fernetti C, Tirolo C, et al. Bilirubin protects astrocytes from its own toxicity by inducing up-regulation and translocation of multidrug resistance-associated protein 1 (Mrp1). Proc Natl Acad Sci USA 2004; 101: 2470-5.
125. Callaghan R, Riordan JR. Synthetic and natural opiates interact with P-glycoprotein in multidrug-resistant cells. J. Biol chem. 1993; 268: 16059-64.
126. Zong J, Pollack GM. Morphine antinociception is enhanced in mdr1a gene-deficent mice. Pharm Res 2000; 17: 749-53.
127. Letrent SP, Pollack GM, Brouver KR, Brouver KLR. Effects of a potent and specific P-glycoprotein inhibitor on the blood brain barrier distribution and antinociceptive effect of morphin in the rat. Drug Metab Disps 1999; 27: 827-34.
128. Chishty M, Reichel A, Siva, J, Abbott N J, Begley D J. Affinity for the P-glycoprotein efflux pump at the blood-brain barrier may explain the lack of CNS side-effects of modern antihistamines. J Drug Targ 2001; 9: 233-88.
129. Polli JW, Baughman TM, Humphreys JE, et al. P-glycoprotein influences the brain concentrations of cetirizine (Zyrtec), a second generation non-sedating antihistamine. J Pharm Sci 2003; 92: 2082-9.
130. Laduron PM, Leysen JE. Domperidone, a specific in vitro dopamine antagonist, devoid of in vivo central dopaminergic activity. Biochem Pharmacol 1979; 28: 2161-5.
131. Schinkel AH, Wagenaar E, Mol CA, van Deemter L. Pglycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest 1996; 97: 2517-24.
132. Yang JZ, Chen W, Borchardt RT. In vitro stability and in vivo pharmacokinetic studies of a model opioid peptide, H-Tyr-D-Ala- Gly-Phe-D-Leu-OH (DADLE), and its cyclic prodrugs. J Pharmacol Exp Ther 2002; 303: 840-8.
133. Ouyang H, Tang F, Siahaan TJ, Borchardt RT. A modified coumarinic acid-based cyclic prodrug of an opioid peptide: its enzymatic and chemical stability and cell permeation characteristics. Pharm Res 2002; 19: 794-801.
134. Chen W, Yang JZ, Andersen R, Nielsen LH, Borchardt RT. Evaluation of the permeation characteristics of a model opioid peptide, H-Tyr-D-Ala-Gly-Phe-D-Leu-OH (DADLE), and its cyclic prodrugs across the blood-brain barrier using an in situ perfused rat brain model. J Pharmacol Exp Ther 2002; 303: 849-57.
135. Liederer BM, Fuchs T, Vander Velde D, Siahaan TJ, Borchardt RT. Effects of amino acid chirality and the chemical linker on the celle permeation characteristics of cyclic prodrugs of opioid peptides. J Med Chem, 2006; 49: 1261-70.
136. Leisen C, Langguth P, Herbert B, Dressler C, Koggel A, Spahn- Langguth H. Lipophilicities of baclofen ester prodrugs correlate with affinities to the ATP-dependent efflux pump P-glycoprotein: relevance for their permeation across the blood-brain barrier? Pharm Res 2003; 20: 772-8.
137. Borst P, Evers R, Kool M, Wijnholds J. A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst 2000; 92: 1295-302.
138. Leggas M, Adachi M, Scheffer GL, Sun D, Wielinga P, Du G, et al. Mrp4 confers resistance to topotecan and protects the brain from chemotherapy. Mol Cell Biol 2004; 24: 7612-21.
139. Nies A, Jedlitschky G, König J, et al. Expression and immunolocalization of the multidrug resistance proteins, MRP1-MRP6 (ABCC1-ABCC6), in human brain. Neuroscience 2004; 129: 349-60.
140. 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: 15665-70.
141. Cooray HC, Blackmore CG, Maskell L, Barrand MA. Localisation of breast cancer resistance protein in microvessel endothelium of human brain. Neuroreport 2002; 13: 2059-63.
142. Cisternino S, Mercier C, Bourasset F, Roux F, Scherrmann JM. Expression, up-regulation, and transport activity of the multidrugresistance protein Abcg2 at the mouse blood-brain barrier. Cancer Res 2004; 64: 3296-301.
143. Dauchy S, Dutheil F, Weaver R, et al. ABC transporters, cytochromes P450 and their main transcription factors: expression at the human blood-brain barrier. J Neurochem 2008; 107: 1518-28.
144. Sweet DH, Miller DS, Pritchard JB, Fujiwara Y, Beier DR, Nigam SK. Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 (Slc22a8)) knockout mice. J Biol Chem 2002; 277: 26934-43.
145. Sykes D, Sweet DH, Lowes S, Nigam SK, Pritchard JB, Miller DS. Organic anion transport in choroid plexus from wild-type and organic anion transporter 3 (Slc22a8)-null mice. Am J Physiol Renal Physiol 2004; 286: F972-8.
146. Mori S, Takanaga H, Ohtsuki S, et al. Rat organic anion transporter 3 (rOAT3) is responsible for brain-to-blood efflux of homovanillic acid at the abluminal membrane of brain capillary endothelial cells. J Cereb Blood Flow Metab 2003; 23: 432-40.
147. Ose A, Ito M, Kusuhara H, et al. Limited brain distribution of [3R, 4R, 5 S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxyl ate phosphate (Ro 64-0802), a pharmacologically active form of oseltamivir, by active efflux across the blood-brain barrier mediated by organic anion transporter 3 (Oat3/Slc22a8) and multidrug resistance-associated protein 4 (Mrp4/Abcc4). Drug Metab Dispos 2009; 37: 315-21.
148. Gao B, Hagenbuch B, Kullak-Ublick GA, Benke D, Aguzzi A, Meier PJ. Organic aniontransporting polypeptides mediate transport of opioid peptides across blood-brain barrier. J Pharmacol Exp Ther 2000; 294: 73-9.
149. Lee W, Glaeser H, Smith LH, et al. Polymorphisms in human organic anion-transporting polypeptide 1A2 (OATP1A2): implications for altered drug disposition and central nervous system drug entry. J Biol Chem 2005; 280: 9610-7.
150. Ohtsuki S, Takizawa T, Takanaga H, et al. In vitro study of the functional expression of organic anion transporting polypeptide 3 at rat choroid plexus epithelial cells and its involvement in the cerebrospinal fluid-to-blood transport of estrone-3-sulfate. Mol Pharmacol 2003; 63: 532-7.
151. Ohtsuki S, Takizawa T, Takanaga H, Hori S, Hosoya K, Terasaki T. Localization of organic anion transporting polypeptide 3 (oatp3) in mouse brain parenchymal and capillary endothelial cells. J Neurochem 2004; 90: 743-9.
152. Zhang H, Song YN, Liu WG, Guo XL, Yu LG. Regulation and role of organic anion-transporting polypeptides (OATPs) in drug delivery at the choroid plexus. J Clin Neurosci 2010; 17: 679-84.
153. Gabathuler R. Approaches to transport therapeutic drugs across the blood-brain barrier to treatbrain diseases. Neurobiol Diseases 2010; 37: 48-57.
154. Filmore D. Breaching the blood-brain barrier. Modern Drug Discovery 2002; 5: 22-4.
155. Pardridge WM. Re-engineering biopharmaceuticals for delivery to brain with molecular Trojan horses. Bioconjug Chem 2008; 19: 1327-38.
156. Pardridge WM. Molecular Trojan horses for blood-brain barrier drug delivery. Curr Opin Pharmacol 2006; 6: 494-500.