Efflux transporters in the bloodbrain interfaces in vitro and in vivo methods and correlations

Expert Opinion on Drug Metabolism and Toxicology

Volumn 8, Issue 4, 2012, Pages 419-431

  Krajcsi, Péter ^a   Jani, Márton ^a   Tóth, Beáta ^a   Erdo, Franciska ^a   Kis, Emese ^a   Beéry, Erzsébet ^a   Sziráki, István ^a  

^a SOLVO BIOTECHNOLOGY   (Hungary)

Author keywords

ABCB1; ABCC4; ABCG2; BCRP; Bloodbrain barrier; Bloodcerebrospinal fluid barrier; Brain microdialysis; Efflux transporters; MRP4; P glycoprotein

Indexed keywords

6 CARBOXYFLUORESCEIN; ADENOSINE TRIPHOSPHATASE; AMPRENAVIR; BREAST CANCER RESISTANCE PROTEIN; BUPIVACAINE; CYCLIC AMP; ERLOTINIB; ITRACONAZOLE; KETOCONAZOLE; LEVOBUPIVACAINE; LICARBAZEPINE; METHYLPREDNISOLONE; PEFLOXACIN; PHENYTOIN; QUINIDINE; RHODAMINE 123; TOPOTECAN; VALPROIC ACID; VALSPODAR; VERAPAMIL; VESICULAR TRANSPORT PROTEIN; ZOSUQUIDAR; ABC TRANSPORTER; CARRIER PROTEIN; DRUG;

AREA UNDER THE CURVE; ASTROCYTE; BLOOD BRAIN BARRIER; CORRELATION ANALYSIS; ENDOTHELIUM CELL; EXTRACELLULAR FLUID; HUMAN; IC 50; IN VITRO STUDY; IN VIVO STUDY; MICRODIALYSIS; MICROVASCULATURE; NONHUMAN; POSITRON EMISSION TOMOGRAPHY; REVIEW; SINGLE PHOTON EMISSION COMPUTER TOMOGRAPHY; ANIMAL; BRAIN; CAPILLARY; CYTOLOGY; DRUG INTERACTION; METABOLISM; MOUSE; PERMEABILITY; PHYSIOLOGY;

MUS;

ANIMALS; ATP-BINDING CASSETTE TRANSPORTERS; BLOOD-BRAIN BARRIER; BRAIN; CAPILLARIES; CARRIER PROTEINS; DRUG INTERACTIONS; ENDOTHELIAL CELLS; HUMANS; MICE; PERMEABILITY; PHARMACEUTICAL PREPARATIONS;

EID: 84858826144     PISSN: 17425255     EISSN: 17447607     Source Type: Journal    
DOI: 10.1517/17425255.2012.668184     Document Type: Review

References (100)

1. Schlageter KE, Molnar P, Lapin GD, et al. Microvessel organization and structure in experimental brain tumors: Microvessel populations with distinctive structural and functional properties. Microvasc Res 1999;58:312-28 Important study on BBB structure.
2. Keep RF, Jones HC. A morphometric study on the development of the lateral ventricle choroid plexus, choroid plexus capillaries and ventricular ependyma in the rat. Brain Res Dev Brain Res 1990;56:47-53 Important study on CP morphology. Good source of important morphometric parameters.
3. Mae M, Armulik A, Betsholtz C. Getting to know the cast - cellular interactions and signaling at the neurovascular unit. Curr Pharm Des 2011;17:2750-4
4. Winkler EA, Bell RD, Zlokovic BV. Central nervous system pericytes in health and disease. Nat Neurosci 2011;14:1398-405
5. Pardridge WM. Drug and gene targeting to the brain with molecular Trojan horses. Nat Rev Drug Discov 2002;1:131-9 Good review on the challenge of getting small molecular drugs as well as biologics into the brain. The review also covers major strategies.
6. Sugiyama D, Kusuhara H, Lee YJ, et al. Involvement of multidrug resistance associated protein 1 (Mrp1) in the efflux transport of 17beta estradiol-D-17betaglucuronide (E217betaG) across the blood-brain barrier. Pharm Res 2003;20:1394-400
7. Urquhart BL, Kim RB. Blood-brain barrier transporters and response to CNS-active drugs. Eur J Clin Pharmacol 2009;65:1063-70 . Good review on BBB resident transporters. Compiles functional data on the significance of transporters in the BBB.
8. Reichel V, Klas J, Fricker G, et al. Fluo-cAMP is transported by multidrug resistance-associated protein isoform 4 in rat choroid plexus. J Neurochem 2010;115:200-8
9. Glavinas H, Mehn D, Jani M, et al. Utilization of membrane vesicle preparations to study drug-ABC transporter interactions. Expert Opin Drug Metab Toxicol 2008;4:721-32 . Reviews membrane assay applications. Provides suggestions on assay selection.
10. Polli JW, Wring SA, Humphreys JE, et al. Rational use of in vitro P-glycoprotein assays in drug discovery. J Pharmacol Exp Ther 2001;299:620-8
11. Giacomini KM, Huang SM, Tweedie DJ, et al. Membrane transporters in drug development. Nat Rev Drug Discov 2010; 9:215-36 . Provides short list of transporters and a regulatory view on DTI testing.
12. von Richter O, Glavinas H, Krajcsi P, et al. A novel screening strategy to identify ABCB1 substrates and inhibitors. Naunyn Schmiedebergs Arch Pharmacol 2009;379:11-26
13. Sauna ZE, Nandigama K, Ambudkar SV. Multidrug resistance protein 4 (ABCC4)- mediated ATP hydrolysis: Effect of transport substrates and characterization of the post-hydrolysis transition state. J Biol Chem 2004;279:48855-64
14. Deli MA, Abraham CS, Kataoka Y, et al. Permeability studies on in vitro blood-brain barrier models: Physiology, pathology, and pharmacology. Cell Mol Neurobiol 2005; 25:59-127 . Extensive review of in vitro approaches to study BBB permeability of small molecules.
15. Butt AM, Jones HC, Abbott NJ. Electrical resistance across the blood-brain barrier in anaesthetized rats: A developmental study. J Physiol 1990;429:47-62
16. Cucullo L, Hossain M, Rapp E, et al. Development of a humanized in vitro blood-brain barrier model to screen for brain penetration of antiepileptic drugs. Epilepsia 2007;48:505-16
17. 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
18. Thanabalasundaram G, Schneidewind J, Pieper C, et al. The impact of pericytes on the blood-brain barrier integrity depends critically on the pericyte differentiation stage. Int J Biochem Cell Biol 2011;43:1284-93
19. Hughes HC. Swine in cardiovascular research. Lab Anim Sci 1986; 36:348-50
20. Veszelka S, Urbanyi Z, Pazmany T, et al. Human serum amyloid P component attenuates the bacterial lipopolysaccharide-induced increase in blood-brain barrier permeability in mice. Neurosci Lett 2003;352:57-60
21. Jiang XL, Gonzalez FJ, Yu AM. Drug-metabolizing enzyme, transporter, and nuclear receptor genetically modified mouse models. Drug Metab Rev 2011;43:27-40
22. Patterson D, Graham C, Cherian C, et al. A humanized mouse model for the reduced folate carrier. Mol Genet Metab 2008;93:95-103
23. Weksler BB, Subileau EA, Perriere N, et al. Blood-brain barrier-specific properties of a human adult brain endothelial cell line. FASEB J 2005;19:1872-4 The paper on generation and initial characterization of hCMEC/D3 cells.
24. Hatherell K, Couraud PO, Romero IA, et al. Development of a three-dimensional, all-human in vitro model of the blood-brain barrier using mono-, co-, and tri-cultivation Transwell models. J Neurosci Methods 2011;199:223-9
25. Tai LM, Reddy PS, Lopez-Ramirez MA, et al. Polarized P-glycoprotein expression by the immortalised human brain endothelial cell line, hCMEC/D3, restricts apical-to-basolateral permeability to rhodamine 123. Brain Res 2009;1292:14-24
26. Cucullo L, Couraud PO, Weksler B, et al. Immortalized human brain endothelial cells and flow-based vascular modeling: A marriage of convenience for rational neurovascular studies. J Cereb Blood Flow Metab 2008;28:312-28
27. Sano Y, Shimizu F, Abe M, et al. Establishment of a new conditionally immortalized human brain microvascular endothelial cell line retaining an in vivo blood-brain barrier function. J Cell Physiol 2010;225:519-28
28. Roux F, Couraud PO. Rat brain endothelial cell lines for the study of blood-brain barrier permeability and transport functions. Cell Mol Neurobiol 2005;25:41-58
29. Lee HT, Chang YC, Tu YF, et al. CREB activation mediates VEGF-A's protection of neurons and cerebral vascular endothelial cells. J Neurochem 2010;113:79-91
30. Hosoya K, Tetsuka K, Nagase K, et al. Conditionally immortalized brain capillary endothelial cell lines established from a transgenic mouse harboring temperature-sensitive simian virus 40 large T-antigen gene. AAPS PharmSci 2000;2:E27
31. Mukwaya G, MacGregor T, Hoelscher D, et al. Interaction of ritonavir-boosted tipranavir with loperamide does not result in loperamide-associated neurologic side effects in healthy volunteers. Antimicrob Agents Chemother 2005;49:4903-10
32. Baehr C, Reichel V, Fricker G. Choroid plexus epithelial monolayers-a cell culture model from porcine brain. Cerebrospinal Fluid Res 2006;3:13
33. Johanson CE, Stopa EG, McMillan PN. The blood-cerebrospinal fluid barrier: Structure and functional significance. Methods Mol Biol 2011;686:101-31
34. Shi LZ, Li GJ, Wang S, et al. Use of Z310 cells as an in vitro blood-cerebrospinal fluid barrier model: Tight junction proteins and transport properties. Toxicol In Vitro 2008;22:190-9
35. Szmydynger-Chodobska J, Pascale CL, Pfeffer AN, et al. Expression of junctional proteins in choroid plexus epithelial cell lines: A comparative study. Cerebrospinal Fluid Res 2007;4:11
36. Yousif S, Marie-Claire C, Roux F, et al. Expression of drug transporters at the blood-brain barrier using an optimized isolated rat brain microvessel strategy. Brain Res 2007;1134:1-11
37. Roberts LM, Black DS, Raman C, et al. Subcellular localization of transporters along the rat blood-brain barrier and blood-cerebral-spinal fluid barrier by in vivo biotinylation. Neuroscience 2008;155:423-38 Elegant study on localization of efflux and some uptake transporters in the BBB.
38. Bachmeier CJ, Trickler WJ, Miller DW. Comparison of drug efflux transport kinetics in various blood-brain barrier models. Drug Metab Dispos 2006;34:998-1003
39. 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;277:1550-9 Description of the BEI method.
40. Camenzind RS, Chip S, Gutmann H, et al. Preservation of transendothelial glucose transporter 1 and P-glycoprotein transporters in a cortical slice culture model of the blood-brain barrier. Neuroscience 2010;170:361-71
41. Kovacs R, Raue C, Gabriel S, et al. Functional test of multidrug transporter activity in hippocampal-neocortical brain slices from epileptic patients. J Neurosci Methods 2011;200:164-72
42. Garberg P, Ball M, Borg N, et al. In vitro models for the blood-brain barrier. Toxicol In Vitro 2005;19:299-334 . Important paper on IVIVC.
43. Hakkarainen JJ, Jalkanen AJ, Kaariainen TM, et al. Comparison of in vitro cell models in predicting in vivo brain entry of drugs. Int J Pharm 2010;402:27-36
44. Lundquist S, Renftel M, Brillault J, et al. Prediction of drug transport through the blood-brain barrier in vivo: A comparison between two in vitro cell models. Pharm Res 2002;19:976-81
45. Glavinas H, von Richter O, Vojnits K, et al. Calcein assay: A high-throughput method to assess P-gp inhibition. Xenobiotica 2011;41:712-19
46. Dash AK, Elmquist WF. Separation methods that are capable of revealing blood-brain barrier permeability. J Chromatogr B Analyt Technol Biomed Life Sci 2003;797:241-54 . An excellent review of in vivo brain permeability measurements. Covers basic computation aspect too.
47. Summerfield SG, Read K, Begley DJ, et al. Central nervous system drug disposition: The relationship between in situ brain permeability and brain free fraction. J Pharmacol Exp Ther 2007;322:205-13 . A good paper on in situ permeability. Also covers correlations with MDCKIIMDR1 permeabilities and lipophilicity.
48. Akanuma S, Ohtsuki S, Doi Y, et al. ATP-binding cassette transporter A1 (ABCA1) deficiency does not attenuate the brain-to-blood efflux transport of human amyloid-beta peptide (1-40) at the blood-brain barrier. Neurochem Int 2008;52:956-61
49. Moriki Y, Suzuki T, Fukami T, et al. Involvement of P-glycoprotein in blood-brain barrier transport of pentazocine in rats using brain uptake index method. Biol Pharm Bull 2004;27:932-5
50. Sakata A, Tamai I, Kawazu K, et al. In vivo evidence for ATP-dependent and P-glycoprotein-mediated transport of cyclosporin A at the blood-brain barrier. Biochem Pharmacol 1994;48:1989-92
51. Westerhout J, Danhof M, De Lange EC. Preclinical prediction of human brain target site concentrations: Considerations in extrapolating to the clinical setting. J Pharm Sci 2011;100:3577-93 A good review on microdialysis.
52. Sziraki I, Erdo F, Beery E, et al. Quinidine as an ABCB1 probe for testing drug interactions at the blood-brain barrier: An in vitro in vivo correlation study. J Biomol Screen 2011;16:886-94
53. Tunblad K, Hammarlund-Udenaes M, Jonsson EN. Influence of probenecid on the delivery of morphine-6-glucuronide to the brain. Eur J Pharm Sci 2005;24:49-57
54. Xie R, Hammarlund-Udenaes M, de Boer AG, et al. The role of P-glycoprotein in blood-brain barrier transport of morphine: Transcortical microdialysis studies in mdr1a (-/-) and mdr1a (+/+) mice. Br J Pharmacol 1999;128:563-8
55. Potschka H, Loscher W. In vivo evidence for P-glycoprotein-mediated transport of phenytoin at the blood-brain barrier of rats. Epilepsia 2001;42:1231-40
56. Mensch J, Oyarzabal J, Mackie C, et al. In vivo, in vitro and in silico methods for small molecule transfer across the BBB. J Pharm Sci 2009;98:4429-68
57. Nicolazzo JA, Charman SA, Charman WN. Methods to assess drug permeability across the blood-brain barrier. J Pharm Pharmacol 2006;58:281-93
58. 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;16:1206-12
59. Miller PW, Long NJ, Vilar R, et al. Synthesis of 11C, 18F, 15O, and 13N radiolabels for positron emission tomography. Angew Chem Int Ed Engl 2008;47:8998-9033
60. Shibata N, Matsnev A, Cahard D. Shelf-stable electrophilic trifluoromethylating reagents: A brief historical perspective. Beilstein J Org Chem 2010;6:65
61. Kannan P, John C, Zoghbi SS, et al. Imaging the function of P-glycoprotein with radiotracers: Pharmacokinetics and in vivo applications. Clin Pharmacol Ther 2009;86:368-77
62. Eyal S, Ke B, Muzi M, et al. Regional P-glycoprotein activity and inhibition at the human blood-brain barrier as imaged by positron emission tomography. Clin Pharmacol Ther 2010;87:579-85
63. Mahar 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;303:1029-37 A nice paper on the profile of CNS and non-CNS drugs.
64. Mahar Doan KM, Wring SA, Shampine LJ, et al. Steady-state brain concentrations of antihistamines in rats: Interplay of membrane permeability, P-glycoprotein efflux and plasma protein binding. Pharmacology 2004;72:92-8
65. Josserand V, Pelerin H, de Bruin B, et al. Evaluation of drug penetration into the brain: A double study by in vivo imaging with positron emission tomography and using an in vitro model of the human blood-brain barrier. J Pharmacol Exp Ther 2006;316:79-86
66. Dehouck MP, Meresse S, Delorme P, et al. An easier, reproducible, and mass-production method to study the blood-brain barrier in vitro. J Neurochem 1990;54:1798-801
67. Warren MS, Zerangue N, Woodford K, et al. Comparative gene expression profiles of ABC transporters in brain microvessel endothelial cells and brain in five species including human. Pharmacol Res 2009;59:404-13
68. Cserr HF, Bundgaard M. Blood-brain interfaces in vertebrates: A comparative approach. Am J Physiol 1984;246:R277-88
69. Feng B, Mills JB, Davidson RE, et al. In vitro P-glycoprotein assays to predict the in vivo interactions of P-glycoprotein with drugs in the central nervous system. Drug Metab Dispos 2008;36:268-75
70. Adachi Y, Suzuki H, Sugiyama Y. Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm Res 2001;18:1660-8
71. Ishiwata K, Kawamura K, Yanai K, et al. In vivo evaluation of P-glycoprotein modulation of 8 PET radioligands used clinically. J Nucl Med 2007;48:81-7
72. von Moltke LL, Granda BW, Grassi JM, et al. Interaction of triazolam and ketoconazole in P-glycoprotein-deficient mice. Drug Metab Dispos 2004;32:800-4
73. Miyama T, Takanaga H, Matsuo H, et al. P-glycoprotein-mediated transport of itraconazole across the blood-brain barrier. Antimicrob Agents Chemother 1998;42:1738-44
74. Robey RW, Massey PR, Amiri-Kordestani L, et al. ABC transporters: Unvalidated therapeutic targets in cancer and the CNS. Anticancer Agents Med Chem 2010;10:625-33
75. Shen J, Carcaboso AM, Hubbard KE, et al. Compartment-specific roles of ATP-binding cassette transporters define differential topotecan distribution in brain parenchyma and cerebrospinal fluid. Cancer Res 2009;69:5885-92
76. Kodaira H, Kusuhara H, Fujita T, et al. Quantitative evaluation of the impact of active efflux by p-glycoprotein and breast cancer resistance protein at the blood-brain barrier on the predictability of the unbound concentrations of drugs in the brain using cerebrospinal fluid concentration as a surrogate. J Pharmacol Exp Ther 2011;339:935-44
77. Tsaioun K, Bottlaender M, Mabondzo A. ADDME-Avoiding Drug Development Mistakes Early: Central nervous system drug discovery perspective. BMC Neurol 2009;9(Suppl 1):S1
78. Megard I, Garrigues A, Orlowski S, et al. A co-culture-based model of human blood-brain barrier: Application to active transport of indinavir and in vivo-in vitro correlation. Brain Res 2002;927:153-67 A nice IVIVC study utilizing multiple in vitro tools.
79. Rajnai Z, Mehn D, Beery E, et al. ATP-binding cassette B1 transports seliciclib (R-roscovitine), a cyclin-dependent kinase inhibitor. Drug Metab Dispos 2010;38:2000-6
80. Uchida Y, Ohtsuki S, Katsukura Y, et al. Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. J Neurochem 2011;117:333-45
81. Takeuchi T, Yoshitomi S, Higuchi T, et al. Establishment and characterization of the transformants stably-expressing MDR1 derived from various animal species in LLC-PK1. Pharm Res 2006;23:1460-72
82. Booth-Genthe CL, Louie SW, Carlini EJ, et al. Development and characterization of LLC-PK1 cells containing Sprague-Dawley rat Abcb1a (Mdr1a): Comparison of rat P-glycoprotein transport to human and mouse. J Pharmacol Toxicol Methods 2006;54:78-89
83. Cecchelli R, Berezowski V, Lundquist S, et al. Modelling of the blood-brain barrier in drug discovery and development. Nat Rev Drug Discov 2007;6:650-61
84. Smith M, Omidi Y, Gumbleton M. Primary porcine brain microvascular endothelial cells: Biochemical and functional characterisation as a model for drug transport and targeting. J Drug Target 2007;15:253-68
85. Omidi Y, Campbell L, Barar J, et al. Evaluation of the immortalised mouse brain capillary endothelial cell line, b. End3, as an in vitro blood-brain barrier model for drug uptake and transport studies. Brain Res 2003;990:95-112
86. Tan KH, Dobbie MS, Felix RA, et al. A comparison of the induction of immortalized endothelial cell impermeability by astrocytes. Neuroreport 2001;12:1329-34
87. Wu YT, Kao YL, Lin LC, et al. Effects of a P-glycoprotein modulator on the pharmacokinetics and distribution of free levobupivacaine and bupivacaine in rats. Int J Pharm 2010;396:127-33
88. Clinckers R, Smolders I, Michotte Y, et al. Impact of efflux transporters and of seizures on the pharmacokinetics of oxcarbazepine metabolite in the rat brain. Br J Pharmacol 2008;155:1127-38
89. Okura T, Ozawa T, Ito Y, et al. Enhancement by grapefruit juice of morphine antinociception. Biol Pharm Bull 2008;31:2338-41
90. Groenendaal D, Freijer J, de Mik D, et al. Population pharmacokinetic modelling of non-linear brain distribution of morphine: Influence of active saturable influx and P-glycoprotein mediated efflux. Br J Pharmacol 2007;151:701-12
91. Edwards JE, Brouwer KR, McNamara PJ. GF120918, a P-glycoprotein modulator, increases the concentration of unbound amprenavir in the central nervous system in rats. Antimicrob Agents Chemother 2002;46:2284-6
92. Potschka H, Fedrowitz M, Loscher W. P-glycoprotein and multidrug resistance-associated protein are involved in the regulation of extracellular levels of the major antiepileptic drug carbamazepine in the brain. Neuroreport 2001;12:3557-60
93. Tsai TH. Pharmacokinetics of pefloxacin and its interaction with cyclosporin A, a P-glycoprotein modulator, in rat blood, brain and bile, using simultaneous microdialysis. Br J Pharmacol 2001;132:1310-16
94. Letrent SP, Pollack GM, Brouwer KR, et al. Effects of a potent and specific P-glycoprotein inhibitor on the blood-brain barrier distribution and antinociceptive effect of morphine in the rat. Drug Metab Dispos 1999;27:827-34
95. Wang Q, Yang H, Miller DW, et al. Effect of the p-glycoprotein inhibitor, cyclosporin A, on the distribution of rhodamine-123 to the brain: An in vivo microdialysis study in freely moving rats. Biochem Biophys Res Commun 1995;211:719-26
96. Baltes S, Fedrowitz M, Tortos CL, et al. Valproic acid is not a substrate for P-glycoprotein or multidrug resistance proteins 1 and 2 in a number of in vitro and in vivo transport assays. J Pharmacol Exp Ther 2007;320:331-43
97. Venkatakrishnan K, Tseng E, Nelson FR, et al. Central nervous system pharmacokinetics of the Mdr1 P-glycoprotein substrate CP-615,003: Intersite differences and implications for human receptor occupancy projections from cerebrospinal fluid exposures. Drug Metab Dispos 2007;35:1341-9
98. Zhuang Y, Fraga CH, Hubbard KE, et al. Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor. Cancer Res 2006;66:11305-13
99. Elmeliegy MA, Carcaboso AM, Tagen M, et al. Role of ATP-binding cassette and solute carrier transporters in erlotinib CNS penetration and intracellular accumulation. Clin Cancer Res 2011;17:89-99
100. Bernards CM. Cyclosporine-A-mediated inhibition of p-glycoprotein increases methylprednisolone entry into the central nervous system. Spinal Cord 2006;44:414-20