Challenges of using in vitro data for modeling P-glycoprotein efflux in the blood-brain barrier

Pharmaceutical Research

Volumn 31, Issue 1, 2014, Pages 1-19

  Sjöstedt, Noora ^a   Kortejärvi, Hanna ^a   Kidron, Heidi ^a   Vellonen, Kati Sisko ^a,b   Urtti, Arto ^a   Yliperttula, Marjo ^a  

^a UNIVERSITY OF HELSINKI   (Finland)

^b UNIVERSITY OF EASTERN FINLAND   (Finland)

Author keywords

blood brain barrier; efflux transport; in vitro in vivo extrapolation; p glycoprotein; physiologically based pharmacokinetic modeling

Indexed keywords

MULTIDRUG RESISTANCE PROTEIN; QUINIDINE;

ARTIFICIAL MEMBRANE; BLOOD BRAIN BARRIER; BRAIN; BRAIN BLOOD VESSEL; BRAIN PERFUSION; BRAIN TISSUE; COMPUTER MODEL; CONCEPTUAL FRAMEWORK; DRUG BINDING; DRUG DISPOSITION; HUMAN; IN VITRO STUDY; MEMBRANE VESICLE; NONHUMAN; PERMEABILITY; PRIORITY JOURNAL; PROTEIN TRANSPORT; QUANTITATIVE STRUCTURE PROPERTY RELATION; REVIEW;

ANIMALS; BIOLOGICAL TRANSPORT; BLOOD-BRAIN BARRIER; CENTRAL NERVOUS SYSTEM AGENTS; HUMANS; P-GLYCOPROTEINS; PERMEABILITY;

EID: 84891616897     PISSN: 07248741     EISSN: 1573904X     Source Type: Journal    
DOI: 10.1007/s11095-013-1124-2     Document Type: Review

References (179)

1. Sugano K, Kansy M, Artursson P, Avdeef A, Bendels S, Di L, et al. Coexistence of passive and carrier-mediated processes in drug transport. Nat Rev Drug Discov. 2010;9(8):597-614.
2. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis. 2010;37(1):13-25.
3. Ohtsuki S, Terasaki T. Contribution of carrier-mediated transport systems to the blood-brain barrier as a supporting and protecting interface for the brain; importance for CNS drug discovery and development. Pharm Res. 2007;24(9):1745-58. (Pubitemid 47206624)
4. Uchida Y, Ohtsuki S, Katsukura Y, Ikeda C, Suzuki T, Kamiie J, et al. Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. J Neurochem. 2011;117(2):333-45.
5. Dauchy S, Dutheil F, Weaver RJ, Chassoux F, Daumas-Duport C, Couraud PO, et al. ABC transporters, cytochromes P450 and their main transcription factors: expression at the human blood-brain barrier. J Neurochem. 2008;107(6):1518-28.
6. Schinkel AH, Smit JJ, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell. 1994;77(4):491-502. (Pubitemid 24153990)
7. Schinkel AH, Wagenaar E, van Deemter L, Mol CA, Borst P. Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest. 1995;96(4):1698-705.
8. Schinkel AH, Wagenaar E, Mol CA, van Deemter L. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest. 1996;97(11):2517-24. (Pubitemid 26187339)
9. Kim RB, Fromm MF, Wandel C, Leake B, Wood AJ, Roden DM, et al. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest. 1998;101(2):289-94. (Pubitemid 28067324)
10. Sadeque AJ, Wandel C, He H, Shah S, Wood AJ. Increased drug delivery to the brain by P-glycoprotein inhibition. Clin Pharmacol Ther. 2000;68(3):231-7.
11. Chen C, Hanson E, Watson JW, Lee JS. P-glycoprotein limits the brain penetration of nonsedating but not sedating H1-antagonists. Drug Metab Dispos. 2003;31(3):312-8. (Pubitemid 36249686)
12. Polli JW, Baughman TM, Humphreys JE, Jordan KH, Mote AL, Salisbury JA, et al. P-glycoprotein influences the brain concentrations of cetirizine (Zyrtec), a second-generation non-sedating antihistamine. J Pharm Sci. 2003;92(10):2082-9. (Pubitemid 37175638)
13. Zhao R, Kalvass JC, Yanni SB, Bridges AS, Pollack GM. Fexofenadine brain exposure and the influence of blood-brain barrier P-glycoprotein after fexofenadine and terfenadine administration. Drug Metab Dispos. 2009;37(3):529-35.
14. Uhr M, Tontsch A, Namendorf C, Ripke S, Lucae S, Ising M, et al. Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression. Neuron. 2008;57(2):203-9.
15. Seelig A. A general pattern for substrate recognition by P-glycoprotein. Eur J Biochem. 1998;251(1-2):252-61. (Pubitemid 28081437)
16. Kamiie J, Ohtsuki S, Iwase R, Ohmine K, Katsukura Y, Yanai K, et al. Quantitative atlas of membrane transporter proteins: development and application of a highly sensitive simultaneous LC/MS/MS method combined with novel in-silico peptide selection criteria. Pharm Res. 2008;25(6):1469-83.
17. Food and Drug Administration. Drug interaction studies - study design, data analysis, implications for dosing, and labeling recommendations (Draft Guidance). 2012. Available from: http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ucm292362.pdf.
18. European Medicines Agency. Guideline on the investigation of drug interactions. 2012.Available from: http://www.ema.europa.eu/docs/en-GB/document- library/Scientific-guideline/2012/07/WC500129606.pdf.
19. Kalvass JC, Polli JW, Bourdet DL, Feng B, Huang S-M, Liu X, et al. Why clinical inhibition of efflux transport at the blood-brain barrier is unlikely: the ITC evidence-based position. Clin Pharmacol Ther. 2013. doi: 10.1038/clpt.2013.34.
20. de Lange ECM, Ravenstijn PGM, Groenendaal D, van Steeg TJ. Toward the prediction of CNS drug-effect profiles in physiological and pathological conditions using microdialysis and mechanism-based pharmacokinetic- pharmacodynamic modeling. AAPS J. 2005;7(3):E532-43.
21. Hammarlund-Udenaes M. Active-site concentrations of chemicals - are they a better predictor of effect than plasma/organ/tissue concentrations? Basic Clin Pharmacol Toxicol. 2010;106(3):215-20.
22. Hammarlund-Udenaes M, Friden M, Syvanen S, Gupta A. On the rate and extent of drug delivery to the brain. Pharm Res. 2008;25(8):1737-50.
23. Bickel U. How to measure drug transport across the blood-brain barrier. NeuroRx. 2005;2(1):15-26. (Pubitemid 40128023)
24. Hammarlund-Udenaes M, Bredberg U, Friden M. Methodologies to assess brain drug delivery in lead optimization. Curr Top Med Chem. 2009;9(2):148-62.
25. Di L, Kerns EH, Carter GT. Strategies to assess blood-brain barrier penetration. Expert Opin Drug Discov. 2008;3(6):677-87. (Pubitemid 351890679)
26. Reichel A. Addressing central nervous system (CNS) penetration in drug discovery: basics and implications of the evolving new concept. Chem Biodivers. 2009;6(11):2030-49.
27. Rowland M. Physiologic pharmacokinetic models and interanimal species scaling. Pharmacol Ther. 1985;29(1):49-68. (Pubitemid 16160378)
28. Rostami-Hodjegan A. Physiologically based pharmacokinetics joined with in vitro-in vivo extrapolation of ADME: a marriage under the arch of systems pharmacology. Clin Pharmacol Ther. 2012;92(1):50-61.
29. Kusuhara H, Sugiyama Y. In vitro-in vivo extrapolation of transporter-mediated clearance in the liver and kidney. Drug Metab Pharmacokinet. 2009;24(1):37-52.
30. Harwood MD, Neuhoff S, Carlson GL, Warhurst G, Rostami-Hodjegan A. Absolute abundance and function of intestinal drug transporters: a prerequisite for fully mechanistic in vitro-in vivo extrapolation of oral drug absorption. Biopharm Drug Dispos. 2012;34(1):2-28.
31. Hammarlund-Udenaes M, Paalzow LK, de Lange EC. Drug equilibration across the blood-brain barrier - pharmacokinetic considerations based on the microdialysis method. Pharm Res. 1997;14(2):128-34. (Pubitemid 27146353)
32. Golden PL, Pollack GM. Rationale for influx enhancement versus efflux blockade to increase drug exposure to the brain. Biopharm Drug Dispos. 1998;19(4):263-72. (Pubitemid 28218422)
33. Upton RN. Theoretical aspects of P-glycoprotein mediated drug efflux on the distribution volume of anaesthetic-related drugs in the brain. Anaesth Intensive Care. 2002;30(2):183-91. (Pubitemid 34406412)
34. Syvanen S, Xie R, Sahin S, Hammarlund-Udenaes M. Pharmacokinetic consequences of active drug efflux at the blood-brain barrier. Pharm Res. 2006;23(4):705-17.
35. Liu X, Smith BJ, Chen C, Callegari E, Becker SL, Chen X, et al. Use of a physiologically based pharmacokinetic model to study the time to reach brain equilibrium: an experimental analysis of the role of blood-brain barrier permeability, plasma protein binding, and brain tissue binding. J Pharmacol Exp Ther. 2005;313(3):1254-62. (Pubitemid 40727030)
36. Bourasset F, Scherrmann JM. Carrier-mediated processes at several rat brain interfaces determine the neuropharmacokinetics of morphine and morphine-6-beta-D-glucuronide. Life Sci. 2006;78(20):2302-14.
37. Groenendaal D, Freijer J, de Mik D, Bouw MR, Danhof M, de Lange EC. 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(5):701-12. (Pubitemid 47016288)
38. Syvanen S, Schenke M, van den Berg DJ, Voskuyl RA, de Lange EC. Alteration in P-glycoprotein functionality affects intrabrain distribution of quinidine more than brain entry- A study in rats subjected to status epilepticus by kainate. AAPS J. 2012;14(1):87-96.
39. Westerhout J, Ploeger B, Smeets J, Danhof M, de Lange EC. Physiologically based pharmacokinetic modeling to investigate regional brain distribution kinetics in rats. AAPS J. 2012;14(3):543-53.
40. Kielbasa W, Stratford Jr RE. Exploratory translational modeling approach in drug development to predict human brain pharmacokinetics and pharmacologically relevant clinical doses. Drug Metab Dispos. 2012;40(5):877-83.
41. Fenneteau F, Turgeon J, Couture L, Michaud V, Li J, Nekka F. Assessing drug distribution in tissues expressing P-glycoprotein through physiologically based pharmacokinetic modeling: model structure and parameters determination. Theor Biol Med Model. 2009;6:2.
42. Ball K, Bouzom F, Scherrmann JM, Walther B, Decleves X. Development of a physiologically based pharmacokinetic model for the rat central nervous system and determination of an in vitro-in vivo scaling methodology for the blood-brain barrier permeability of two transporter substrates, morphine and oxycodone. J Pharm Sci. 2012;101(11):4277-92.
43. Bouzom F, Ball K, Perdaems N, Walther B. Physiologically based pharmacokinetic (PBPK) modelling tools: how to fit with our needs? Biopharm Drug Dispos. 2012;33(2):55-71.
44. Gjedde A, Christensen O. Estimates of Michaelis-Menten constants for the two membranes of the brain endothelium. J Cereb Blood Flow Metab. 1984;4(2):241-9. (Pubitemid 14080153)
45. 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):H484-93.
46. 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):H1022-8.
47. 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):381-6. (Pubitemid 30108457)
48. Avdeef A, Sun N. A new in situ brain perfusion flow correction method for lipophilic drugs based on the pH-dependent Crone-Renkin equation. Pharm Res. 2011;28(3):517-30.
49. Cisternino S, Rousselle C, Dagenais C, Scherrmann JM. Screening of multidrug-resistance sensitive drugs by in situ brain perfusion in P-glycoprotein-deficient mice. Pharm Res. 2001;18(2):183-90. (Pubitemid 32592598)
50. Umbenhauer DR, Lankas GR, Pippert TR, Wise LD, Cartwright ME, Hall SJ, et al. Identification of a P-glycoprotein-deficient subpopulation in the CF-1 mouse strain using a restriction fragment length polymorphism. Toxicol Appl Pharmacol. 1997;146(1):88-94. (Pubitemid 27406400)
51. Chu X, Zhang Z, Yabut J, Horwitz S, Levorse J, Li XQ, et al. Characterization of multidrug resistance 1a/P-glycoprotein knockout rats generated by zinc finger nucleases. Mol Pharmacol. 2012;81(2):220-7.
52. Zamek-Gliszczynski MJ, Bedwell DW, Bao JQ, Higgins JW. Characterization of SAGE Mdr1a (P-gp), Bcrp, and Mrp2 knockout rats using loperamide, paclitaxel, sulfasalazine, and carboxydichlorofluorescein pharmacokinetics. Drug Metab Dispos. 2012;40(9):1825-33.
53. Jonker JW, Buitelaar M, Wagenaar E, Van Der Valk MA, Scheffer GL, Scheper RJ, et al. The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Proc Natl Acad Sci U S A. 2002;99(24):15649-54. (Pubitemid 35403986)
54. Agarwal S, Uchida Y, Mittapalli RK, Sane R, Terasaki T, Elmquist WF. Quantitative proteomics of transporter expression in brain capillary endothelial cells isolated from P-glycoprotein (P-gp), breast cancer resistance protein (Bcrp), and P-gp/Bcrp knockout mice. Drug Metab Dispos. 2012;40(6):1164-9.
55. Gumbleton M, Audus KL. Progress and limitations in the use of in vitro cell cultures to serve as a permeability screen for the blood-brain barrier. J Pharm Sci. 2001;90(11):1681-98. (Pubitemid 33062590)
56. Reichel A, Begley DJ, Abbott NJ. An overview of in vitro techniques for blood-brain barrier studies. Methods Mol Med. 2003;89:307-24.
57. Deli MA, Abraham CS, Kataoka Y, Niwa M. Permeability studies on in vitro blood-brain barrier models: physiology, pathology, and pharmacology. Cell Mol Neurobiol. 2005;25(1):59-127. (Pubitemid 40558585)
58. 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. (Pubitemid 20327537)
59. Garberg P, Ball M, Borg N, Cecchelli R, Fenart L, Hurst RD, et al. In vitro models for the blood-brain barrier. Toxicol In Vitro. 2005;19(3):299-334. (Pubitemid 40248750)
60. 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):976-81. (Pubitemid 34804239)
61. Polli JW, Humphreys JE, Wring SA, Burnette TC, Read KD, Hersey A, et al. A comparison of Madin-Darby canine kidney cells and bovine brain endothelial cells as a blood-brain barrier screen in early drug discovery. Progress in the Reduction, Refinement and Replacement of Animal Experimentation. 2000;31:271-89.
62. Feng B, Mills JB, Davidson RE, Mireles RJ, Janiszewski JS, Troutman MD, 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(2):268-75. (Pubitemid 351185738)
63. Wang Q, Rager JD, Weinstein K, Kardos PS, Dobson GL, Li J, et al. Evaluation of the MDR-MDCK cell line as a permeability screen for the blood-brain barrier. Int J Pharm. 2005;288(2):349-59. (Pubitemid 40038588)
64. 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(12):1660-8. (Pubitemid 34020420)
65. Braun A, Hammerle S, Suda K, Rothen-Rutishauser B, Gunthert M, Kramer SD, et al. Cell cultures as tools in biopharmacy. Eur J Pharm Sci. 2000;11 Suppl 2:S51-60.
66. van der Sandt IC, Blom-Roosemalen MC, de Boer AG, Breimer DD. Specificity of doxorubicin versus rhodamine-123 in assessing P-glycoprotein functionality in the LLC-PK1, LLC-PK1:MDR1 and Caco-2 cell lines. Eur J Pharm Sci. 2000;11(3):207-14. (Pubitemid 30616443)
67. Dukes JD, Whitley P, Chalmers AD. The MDCK variety pack: choosing the right strain. BMC Cell Biol. 2011;12:43.
68. Goh LB, Spears KJ, Yao D, Ayrton A, Morgan P, Roland Wolf C, et al. Endogenous drug transporters in in vitro and in vivo models for the prediction of drug disposition in man. Biochem Pharmacol. 2002;64(11):1569-78. (Pubitemid 35333418)
69. Kuteykin-Teplyakov K, Luna-Tortos C, Ambroziak K, Loscher W. Differences in the expression of endogenous efflux transporters in MDR1-transfected versus wildtype cell lines affect P-glycoprotein mediated drug transport. Br J Pharmacol. 2010;160(6):1453-63.
70. Di L, Whitney-Pickett C, Umland JP, Zhang H, Zhang X, Gebhard DF, et al. Development of a new permeability assay using low-efflux MDCKII cells. J Pharm Sci. 2011;100(11):4974-85.
71. Hellinger E, Veszelka S, Toth AE, Walter F, Kittel A, Bakk ML, et al. Comparison of brain capillary endothelial cell-based and epithelial (MDCK-MDR1, Caco-2, and VB-Caco-2) cell-based surrogate blood-brain barrier penetration models. Eur J Pharm Biopharm. 2012;82(2):340-51.
72. Di L, Kerns EH, Bezar IF, Petusky SL, Huang Y. Comparison of blood-brain barrier permeability assays: in situ brain perfusion, MDR1-MDCKII and PAMPA-BBB. J Pharm Sci. 2009;98(6):1980-91.
73. Summerfield SG, Read K, Begley DJ, Obradovic T, Hidalgo IJ, Coggon S, et al. Central nervous system drug disposition: the relationship between in situ brain permeability and brain free fraction. J Pharmacol Exp Ther. 2007;322(1):205-13. (Pubitemid 46956363)
74. Perriere N, Yousif S, Cazaubon S, Chaverot N, Bourasset F, Cisternino S, et al. A functional in vitro model of rat blood-brain barrier for molecular analysis of efflux transporters. Brain Res. 2007;1150:1-13. (Pubitemid 46711185)
75. Zhang Y, Li CS, Ye Y, Johnson K, Poe J, Johnson S, et al. Porcine brain microvessel endothelial cells as an in vitro model to predict in vivo blood-brain barrier permeability. Drug Metab Dispos. 2006;34(11):1935-43. (Pubitemid 44771724)
76. Pardridge WM, Triguero D, Yang J, Cancilla PA. Comparison of in vitro and in vivo models of drug transcytosis through the blood-brain barrier. J Pharmacol Exp Ther. 1990;253(2):884-91. (Pubitemid 20181741)
77. Culot M, Lundquist S, Vanuxeem D, Nion S, Landry C, Delplace Y, et al. An in vitro blood-brain barrier model for high throughput (HTS) toxicological screening. Toxicol In Vitro. 2008;22(3):799-811.
78. Weksler BB, Subileau EA, Perriere N, Charneau P, Holloway K, Leveque M, et al. Blood-brain barrier-specific properties of a human adult brain endothelial cell line. FASEB J. 2005;19(13):1872-4. (Pubitemid 41598779)
79. Youdim KA, Avdeef A, Abbott NJ. In vitro trans-monolayer permeability calculations: often forgotten assumptions. Drug Discov Today. 2003;8(21):997-1003. (Pubitemid 37468418)
80. Triguero D, Buciak J, Pardridge WM. Capillary depletion method for quantification of blood-brain barrier transport of circulating peptides and plasma proteins. J Neurochem. 1990;54(6):1882-8.
81. Avdeef A. How well can in vitro brain microcapillary endothelial cell models predict rodent in vivo blood-brain barrier permeability? Eur J Pharm Sci. 2011;43(3):109-24.
82. Karlsson J, Artursson P. A method for the determination of cellular permeability coefficients and aqueous boundary-layer thickness in monolayers of intestinal epithelial (Caco-2) cells grown in permeable filter chambers. Int J Pharm. 1991;71(1-2):55-64.
83. Hakkarainen JJ, Jalkanen AJ, Kaariainen TM, Keski-Rahkonen P, Venalainen T, Hokkanen J, et al. Comparison of in vitro cell models in predicting in vivo brain entry of drugs. Int J Pharm. 2010;402(1-2):27-36.
84. Crone C. The permeability of capillaries in various organs as determined by use of the 'indicator diffusion' method. Acta Physiol Scand. 1963;58:292-305.
85. Ohno K, Pettigrew KD, Rapoport SI. Lower limits of cerebrovascular permeability to nonelectrolytes in the conscious rat. Am J Physiol. 1978;235(3):H299-307.
86. Kansy M, Senner F, Gubernator K. Physicochemical high throughput screening: parallel artificial membrane permeation assay in the description of passive absorption processes. J Med Chem. 1998;41(7):1007-10. (Pubitemid 28207375)
87. Di L, Kerns EH, Fan K, McConnell OJ, Carter GT. High throughput artificial membrane permeability assay for blood-brain barrier. Eur J Med Chem. 2003;38(3):223-32. (Pubitemid 36349665)
88. Mensch J, Jaroskova L, Sanderson W, Melis A, Mackie C, Verreck G, et al. Application of PAMPA-models to predict BBB permeability including efflux ratio, plasma protein binding and physicochemical parameters. Int J Pharm. 2010;395(1-2):182-97.
89. Mensch J, Melis A, Mackie C, Verreck G, Brewster ME, Augustijns P. Evaluation of various PAMPA models to identify the most discriminating method for the prediction of BBB permeability. Eur J Pharm Biopharm. 2010;74(3):495-502.
90. Carrara S, Reali V, Misiano P, Dondio G, Bigogno C. Evaluation of in vitro brain penetration: optimized PAMPA and MDCKII-MDR1 assay comparison. Int J Pharm. 2007;345(1-2):125-33. (Pubitemid 350103647)
91. von Richter O, Glavinas H, Krajcsi P, Liehner S, Siewert B, Zech K. A novel screening strategy to identify ABCB1 substrates and inhibitors. Naunyn Schmiedeberg's Arch Pharmacol. 2009;379(1):11-26.
92. Tsinman O, Tsinman K, Sun N, Avdeef A. Physicochemical selectivity of the BBB microenvironment governing passive diffusion-matching with a porcine brain lipid extract artificial membrane permeability model. Pharm Res. 2011;28(2):337-63.
93. Fujikawa M, Nakao K, Shimizu R, Akamatsu M. QSAR study on permeability of hydrophobic compounds with artificial membranes. Bioorg Med Chem. 2007;15(11):3756-67. (Pubitemid 46635142)
94. Ruell JA, Tsinman KL, Avdeef A. PAMPA - a drug absorption in vitro model. 5. Unstirred water layer in iso-pH mapping assays and pKa(flux) - optimized design (pOD-PAMPA). Eur J Pharm Sci. 2003;20(4-5):393-402. (Pubitemid 37491433)
95. Dagenais C, Avdeef A, Tsinman O, Dudley A, Beliveau R. P-glycoprotein deficient mouse in situ blood-brain barrier permeability and its prediction using an in combo PAMPA model. Eur J Pharm Sci. 2009;38(2):121-37.
96. Norinder U, Haeberlein M. Computational approaches to the prediction of the blood-brain distribution. Adv Drug Deliv Rev. 2002;54(3):291-313. (Pubitemid 34260955)
97. Clark DE. In silico prediction of blood-brain barrier permeation. Drug Discov Today. 2003;8(20):927-33. (Pubitemid 37230012)
98. Gratton JA, Abraham MH, Bradbury MW, Chadha HS. Molecular factors influencing drug transfer across the blood-brain barrier. J Pharm Pharmacol. 1997;49(12):1211-6. (Pubitemid 28022220)
99. Abraham MH. The factors that influence permeation across the blood-brain barrier. Eur J Med Chem. 2004;39(3):235-40. (Pubitemid 38393750)
100. Liu X, Tu M, Kelly RS, Chen C, Smith BJ. Development of a computational approach to predict blood-brain barrier permeability. Drug Metab Dispos. 2004;32(1):132-9. (Pubitemid 38112545)
101. Lanevskij K, Japertas P, Didziapetris R, Petrauskas A. Ionization-specific prediction of blood-brain permeability. J Pharm Sci. 2009;98(1):122-34.
102. Abraham MH. Scales of solute hydrogen-bonding - their construction and application to physicochemical and biochemical processes. Chem Soc Rev. 1993;22(2):73-83.
103. Linnankoski J, Makela JM, Ranta VP, Urtti A, Yliperttula M. Computational prediction of oral drug absorption based on absorption rate constants in humans. J Med Chem. 2006;49(12):3674-81. (Pubitemid 43902473)
104. Sharom FJ. Shedding light on drug transport: structure and function of the P-glycoprotein multidrug transporter (ABCB1). Biochem Cell Biol. 2006;84(6):979-92. (Pubitemid 46450697)
105. Shapiro AB, Ling V. Positively cooperative sites for drug transport by P-glycoprotein with distinct drug specificities. Eur J Biochem. 1997;250(1):130-7. (Pubitemid 27504592)
106. 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):624-32.
107. Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, et al. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science. 2009;323(5922):1718-22.
108. Polli JW, Wring SA, Humphreys JE, Huang L, Morgan JB, Webster LO, et al. Rational use of in vitro P-glycoprotein assays in drug discovery. J Pharmacol Exp Ther. 2001;299(2):620-8. (Pubitemid 32979675)
109. Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215-36.
110. Uchida Y, Ohtsuki S, Kamiie J, Terasaki T. Blood-brain barrier (BBB) pharmacoproteomics: reconstruction of in vivo brain distribution of 11 P-glycoprotein substrates based on the BBB transporter protein concentration, in vitro intrinsic transport activity, and unbound fraction in plasma and brain in mice. J Pharmacol Exp Ther. 2011;339(2):579-88.
111. Mahar Doan KM, Humphreys JE, Webster LO, Wring SA, Shampine LJ, Serabjit-Singh CJ, 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):1029-37. (Pubitemid 35424386)
112. Bentz J, Tran TT, Polli JW, Ayrton A, Ellens H. The steady-state Michaelis-Menten analysis of P-glycoprotein mediated transport through a confluent cell monolayer cannot predict the correct Michaelis constant Km. Pharm Res. 2005;22(10):1667-77. (Pubitemid 41355906)
113. Litman T, Zeuthen T, Skovsgaard T, Stein WD. Structure-activity relationships of P-glycoprotein interacting drugs: kinetic characterization of their effects on ATPase activity. Biochim Biophys Acta. 1997;1361(2):159-68. (Pubitemid 27362089)
114. Troutman MD, Thakker DR. Novel experimental parameters to quantify the modulation of absorptive and secretory transport of compounds by P-glycoprotein in cell culture models of intestinal epithelium. Pharm Res. 2003;20(8):1210-24. (Pubitemid 36951846)
115. Collett A, Tanianis-Hughes J, Hallifax D, Warhurst G. Predicting P-glycoprotein effects on oral absorption: correlation of transport in Caco-2 with drug pharmacokinetics in wild-type and mdr1a(-/-) mice in vivo. Pharm Res. 2004;21(5):819-26. (Pubitemid 39011306)
116. Tran TT, Mittal A, Aldinger T, Polli JW, Ayrton A, Ellens H, et al. The elementary mass action rate constants of P-gp transport for a confluent monolayer of MDCKII-hMDR1 cells. Biophys J. 2005;88(1):715-38. (Pubitemid 40070714)
117. Glavinas H, Mehn D, Jani M, Oosterhuis B, Heredi-Szabo K, Krajcsi P. Utilization of membrane vesicle preparations to study drug-ABC transporter interactions. Expert Opin Drug Metab Toxicol. 2008;4(6):721-32. (Pubitemid 352003195)
118. Heikkinen AT, Monkkonen J. Protein concentration and pH affect the apparent P-glycoprotein-ATPase activation kinetics. Int J Pharm. 2008;346(1-2):169-72. (Pubitemid 350101985)
119. Gimpl G, Klein U, Reilander H, Fahrenholz F. Expression of the human oxytocin receptor in baculovirus-infected insect cells - high-affinity binding is induced by a cholesterol cyclodextrin complex. Biochemistry. 1995;34(42):13794-801.
120. Marheineke K, Grunewald S, Christie W, Reilander H. Lipid composition of Spodoptera frugiperda (Sf9) and Trichoplusia ni (Tn) insect cells used for baculovirus infection. FEBS Lett. 1998;441(1):49-52. (Pubitemid 29012370)
121. Kimura Y, Kioka N, Kato H, Matsuo M, Ueda K. Modulation of drug-stimulated ATPase activity of human MDR1/P-glycoprotein by cholesterol. Biochem J. 2007;401:597-605. (Pubitemid 46166441)
122. Eckford PDW, Sharom FJ. Interaction of the P-glycoprotein multidrug efflux pump with cholesterol: effects on ATPase activity, drug binding and transport. Biochemistry. 2008;47(51):13686-98.
123. Sarkadi B, Price EM, Boucher RC, Germann UA, Scarborough GA. Expression of the human multidrug resistance Cdna in insect cells generates a high-activity drug-stimulated membrane atpase. J Biol Chem. 1992;267(7):4854-8.
124. Horio M, Gottesman MM, Pastan I. ATP-dependent transport of vinblastine in vesicles from human multidrug-resistant cells. Proc Natl Acad Sci U S A. 1988;85(10):3580-4.
125. Doige CA, Sharom FJ. Transport properties of P-glycoprotein in plasma membrane vesicles from multidrug-resistant Chinese hamster ovary cells. Biochim Biophys Acta. 1992;1109(2):161-71.
126. Gao J, Murase O, Schowen RL, Aube J, Borchardt RT. A functional assay for quantitation of the apparent affinities of ligands of P-glycoprotein in Caco-2 cells. Pharm Res. 2001;18(2):171-6. (Pubitemid 32592596)
127. Tang F, Horie K, Borchardt RT. Are MDCK cells transfected with the human MRP2 gene a good model of the human intestinal mucosa? Pharm Res. 2002;19(6):773-9. (Pubitemid 34686735)
128. Shirasaka Y, Onishi Y, Sakurai A, Nakagawa H, Ishikawa T, Yamashita S. Evaluation of human P-glycoprotein (MDR1/ABCB1) ATPase activity assay method by comparing with in vitro transport measurements: Michaelis-Menten kinetic analysis to estimate the affinity of P-glycoprotein to drugs. Biol Pharm Bull. 2006;29(12):2465-71. (Pubitemid 44885870)
129. Korjamo T, Kemilainen H, Heikkinen AT, Monkkonen J. Decrease in intracellular concentration causes the shift in Km value of efflux pump substrates. Drug Metab Dispos. 2007;35(9):1574-9. (Pubitemid 47296050)
130. Shirasaka Y, Sakane T, Yamashita S. Effect of P-glycoprotein expression levels on the concentration-dependent permeability of drugs to the cell membrane. J Pharm Sci. 2008;97(1):553-65.
131. Heikkinen AT, Korjamo T, Lepikko V, Monkkonen J. Effects of experimental setup on the apparent concentration dependency of active efflux transport in in vitro cell permeation experiments. Mol Pharm. 2010;7(2):605-17.
132. Sugano K, Shirasaka Y, Yamashita S. Estimation of Michaelis-Menten constant of efflux transporter considering asymmetric permeability. Int J Pharm. 2011;418(2):161-7.
133. Heikkinen AT, Korjamo T, Monkkonen J. Modelling of drug disposition kinetics in in vitro intestinal absorption cell models. Basic Clin Pharmacol Toxicol. 2010;106(3):180-8.
134. Tachibana T, Kitamura S, Kato M, Mitsui T, Shirasaka Y, Yamashita S, et al. Model analysis of the concentration-dependent permeability of P-gp substrates. Pharm Res. 2010;27(3):442-6.
135. Korzekwa KR, Nagar S, Tucker J, Weiskircher EA, Bhoopathy S, Hidalgo IJ. Models to predict unbound intracellular drug concentrations in the presence of transporters. Drug Metab Dispos. 2012;40(5):865-76.
136. Kalvass JC, Pollack GM. Kinetic considerations for the quantitative assessment of efflux activity and inhibition: implications for understanding and predicting the effects of efflux inhibition. Pharm Res. 2007;24(2):265-76. (Pubitemid 46072186)
137. Sun H, Pang KS. Permeability, transport, and metabolism of solutes in Caco-2 cell monolayers: a theoretical study. Drug Metab Dispos. 2008;36(1):102-23.
138. Winne D. Unstirred layer, source of biased Michaelis constant in membrane transport. Biochim Biophys Acta. 1973;298(1):27-31.
139. Balakrishnan A, Hussainzada N, Gonzalez P, Bermejo M, Swaan PW, Polli JE. Bias in estimation of transporter kinetic parameters from overexpression systems: Interplay of transporter expression level and substrate affinity. J Pharmacol Exp Ther. 2007;320(1):133-44. (Pubitemid 46025728)
140. Troutman MD, Thakker DR. Efflux ratio cannot assess P-glycoprotein- mediated attenuation of absorptive transport: asymmetric effect of P-glycoprotein on absorptive and secretory transport across Caco-2 cell monolayers. Pharm Res. 2003;20(8):1200-9. (Pubitemid 36951845)
141. Kalvass JC, Maurer TS. Influence of nonspecific brain and plasma binding on CNS exposure: implications for rational drug discovery. Biopharm Drug Dispos. 2002;23(8):327-38. (Pubitemid 36124162)
142. Wang Y, Welty DF. The simultaneous estimation of the influx and efflux blood-brain barrier permeabilities of gabapentin using a microdialysis- pharmacokinetic approach. Pharm Res. 1996;13(3):398-403.
143. 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):1550-9. (Pubitemid 27167171)
144. Friden M, Gupta A, Antonsson M, Bredberg U, Hammarlund-Udenaes M. In vitro methods for estimating unbound drug concentrations in the brain interstitial and intracellular fluids. Drug Metab Dispos. 2007;35(9):1711-9. (Pubitemid 47296068)
145. Friden M, Ducrozet F, Middleton B, Antonsson M, Bredberg U, Hammarlund-Udenaes M. Development of a high-throughput brain slice method for studying drug distribution in the central nervous system. Drug Metab Dispos. 2009;37(6):1226-33.
146. Becker S, Liu X. Evaluation of the utility of brain slice methods to study brain penetration. Drug Metab Dispos. 2006;34(5):855-61.
147. Friden M, Bergstrom F, Wan H, Rehngren M, Ahlin G, Hammarlund-Udenaes M, et al. Measurement of unbound drug exposure in brain: modeling of pH partitioning explains diverging results between the brain slice and brain homogenate methods. Drug Metab Dispos. 2011;39(3):353-62.
148. Wan H, Rehngren M, Giordanetto F, Bergstrom F, Tunek A. High-throughput screening of drug-brain tissue binding and in silico prediction for assessment of central nervous system drug delivery. J Med Chem. 2007;50(19):4606-15. (Pubitemid 47463235)
149. Grandvuinet AS, Vestergaard HT, Rapin N, Steffansen B. Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug-drug interactions. J Pharm Pharmacol. 2012;64(11):1523-48.
150. Miliotis T, Ali L, Palm JE, Lundqvist AJ, Ahnoff M, Andersson TB, et al. Development of a highly sensitive method using liquid chromatography-multiple reaction monitoring to quantify membrane P-glycoprotein in biological matrices and relationship to transport function. Drug Metab Dispos. 2011;39(12):2440-9.
151. Zhang Y, Li N, Brown PW, Ozer JS, Lai Y. Liquid chromatography/tandem mass spectrometry based targeted proteomics quantification of P-glycoprotein in various biological samples. Rapid Commun Mass Spectrom. 2011;25(12):1715-24.
152. Ito K, Uchida Y, Ohtsuki S, Aizawa S, Kawakami H, Katsukura Y, et al. Quantitative membrane protein expression at the blood-brain barrier of adult and younger cynomolgus monkeys. J Pharm Sci. 2011;100(9):3939-50.
153. Ohtsuki S, Uchida Y, Kubo Y, Terasaki T. Quantitative targeted absolute proteomics-based ADME research as a new path to drug discovery and development: methodology, advantages, strategy, and prospects. J Pharm Sci. 2011;100(9):3547-59.
154. Saubamea B, Cochois-Guegan V, Cisternino S, Scherrmann JM. Heterogeneity in the rat brain vasculature revealed by quantitative confocal analysis of endothelial barrier antigen and P-glycoprotein expression. J Cereb Blood Flow Metab. 2012;32(1):81-92.
155. Liu X, Van Natta K, Yeo H, Vilenski O, Weller PE, Worboys PD, et al. Unbound drug concentration in brain homogenate and cerebral spinal fluid at steady state as a surrogate for unbound concentration in brain interstitial fluid. Drug Metab Dispos. 2009;37(4):787-93.
156. Yamazaki M, Neway WE, Ohe T, Chen I, Rowe JF, Hochman JH, et al. In vitro substrate identification studies for p-glycoprotein-mediated transport: species difference and predictability of in vivo results. J Pharmacol Exp Ther. 2001;296(3):723-35. (Pubitemid 32187340)
157. Xia CQ, Xiao G, Liu N, Pimprale S, Fox L, Patten CJ, et al. Comparison of species differences of P-glycoproteins in beagle dog, rhesus monkey, and human using Atpase activity assays. Mol Pharm. 2006;3(1):78-86. (Pubitemid 43331754)
158. Katoh M, Suzuyama N, Takeuchi T, Yoshitomi S, Asahi S, Yokoi T. Kinetic analyses for species differences in P-glycoprotein-mediated drug transport. J Pharm Sci. 2006;95(12):2673-83. (Pubitemid 46093174)
159. Takeuchi T, Yoshitomi S, Higuchi T, Ikemoto K, Niwa S, Ebihara T, et al. Establishment and characterization of the transformants stably-expressing MDR1 derived from various animal species in LLC-PK1. Pharm Res. 2006;23(7):1460-72. (Pubitemid 43993809)
160. Baltes S, Gastens AM, Fedrowitz M, Potschka H, Kaever V, Loscher W. Differences in the transport of the antiepileptic drugs phenytoin, levetiracetam and carbamazepine by human and mouse P-glycoprotein. Neuropharmacology. 2007;52(2):333-46. (Pubitemid 46123353)
161. Syvanen S, Lindhe O, Palner M, Kornum BR, Rahman O, Langstrom B, et al. Species differences in blood-brain barrier transport of three positron emission tomography radioligands with emphasis on P-glycoprotein transport. Drug Metab Dispos. 2009;37(3):635-43.
162. Ouyang H, Andersen TE, Chen W, Nofsinger R, Steffansen B, Borchardt RT. A comparison of the effects of p-glycoprotein inhibitors on the blood-brain barrier permeation of cyclic prodrugs of an opioid peptide (DADLE). J Pharm Sci. 2009;98(6):2227-36.
163. Di L, Umland JP, Chang G, Huang Y, Lin Z, Scott DO, et al. Species independence in brain tissue binding using brain homogenates. Drug Metab Dispos. 2011;39(7):1270-7.
164. Summerfield SG, Lucas AJ, Porter RA, Jeffrey P, Gunn RN, Read KR, et al. Toward an improved prediction of human in vivo brain penetration. Xenobiotica. 2008;38(12):1518-35.
165. Kalvass JC, Maurer TS, Pollack GM. Use of plasma and brain unbound fractions to assess the extent of brain distribution of 34 drugs: comparison of unbound concentration ratios to in vivo p-glycoprotein efflux ratios. Drug Metab Dispos. 2007;35(4):660-6. (Pubitemid 46513270)
166. Friden M, Winiwarter S, Jerndal G, Bengtsson O, Wan H, Bredberg U, et al. Structure-brain exposure relationships in rat and human using a novel data set of unbound drug concentrations in brain interstitial and cerebrospinal fluids. J Med Chem. 2009;52(20):6233-43.
167. de Lange ECM, Danhof M. Considerations in the use of cerebrospinal fluid pharmacokinetics to predict brain target concentrations in the clinical setting - Implications of the barriers between blood and brain. Clin Pharmacokinet. 2002;41(10):691-703. (Pubitemid 34948192)
168. de Lange EC, Danhof M, de Boer AG, Breimer DD. Methodological considerations of intracerebral microdialysis in pharmacokinetic studies on drug transport across the blood-brain barrier. Brain Res Brain Res Rev. 1997;25(1):27-49. (Pubitemid 27459719)
169. Cunningham VJ, Parker CA, Rabiner EA, Gee AD, Gunn RN. PET studies in drug development: methodological considerations. Drug Discov Today Technol. 2005;2(4):311-5. (Pubitemid 43115466)
170. Syvanen S, Hammarlund-Udenaes M. Using PET studies of P-gp function to elucidate mechanisms underlying the disposition of drugs. Curr Top Med Chem. 2010;10(17):1799-809.
171. Gunn RN, Summerfield SG, Salinas CA, Read KD, Guo Q, Searle GE, et al. Combining PET biodistribution and equilibrium dialysis assays to assess the free brain concentration and BBB transport of CNS drugs. J Cereb Blood Flow Metab. 2012;32(5):874-83.
172. Rowland M, Peck C, Tucker G. Physiologically-based pharmacokinetics in drug development and regulatory science. Annu Rev Pharmacol Toxicol. 2011;51:45-73.
173. Kodaira H, Kusuhara H, Ushiki J, Fuse E, Sugiyama Y. Kinetic analysis of the cooperation of P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp/Abcg2) in limiting the brain and testis penetration of erlotinib, flavopiridol, and mitoxantrone. J Pharmacol Exp Ther. 2010;333(3):788-96.
174. 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(2):849-57. (Pubitemid 35231262)
175. Dagenais C, Zong J, Ducharme J, Pollack GM. Effect of mdr1a P-glycoprotein gene disruption, gender, and substrate concentration on brain uptake of selected compounds. Pharm Res. 2001;18(7):957-63. (Pubitemid 32799940)
176. Zhao R, Kalvass JC, Pollack GM. Assessment of blood-brain barrier permeability using the in situ mouse brain perfusion technique. Pharm Res. 2009;26(7):1657-64.
177. Bradbury MW. The concept of a blood-brain barrier. Chichester: Wiley; 1979.
178. Shawahna R, Uchida Y, Decleves X, Ohtsuki S, Yousif S, Dauchy S, et al. Transcriptomic and quantitative proteomic analysis of transporters and drug metabolizing enzymes in freshly isolated human brain microvessels. Mol Pharm. 2011;8(4):1332-41.
179. Ohtsuki S, Ikeda C, Uchida Y, Sakamoto Y, Miller F, Glacial F, et al. Quantitative targeted absolute proteomic analysis of transporters, receptors and junction proteins for validation of human cerebral microvascular endothelial cell line hCMEC/D3 as a human blood-brain barrier model. Mol Pharm. 2013;10(1):289-96.