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In Vivo Approaches to Assessing the Blood–Brain Barrier

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The Blood Brain Barrier (BBB)

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 10))

Abstract

Methods for in vivo assessment of blood-brain barrier (BBB) transport are presented, with their advantages and disadvantages. The methods described are brain uptake index, the i.v. injection technique, in situ brain perfusion, brain efflux index, % injected dose, microdialysis, CSF sampling and positron emission tomography, and the combinatorial mapping of unbound drug partitioning across the BBB. The methods are put into a pharmacokinetic context by delineating the type of readings that they give, be it the rate of transport across the BBB or the extent of transport of total drug (unbound and bound), or of the unbound drug.

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Abbreviations

%ID:

Percentage of the injected dose

A :

Capillary surface area (also denoted S in the literature)

AUC:

Area under the concentration–time curve

BBB:

Blood–brain barrier

BCRP:

Breast cancer resistance protein

BCSFB:

Blood–cerebrospinal fluid barrier

BEI:

Brain efflux index

BUI:

Brain uptake index

C blood :

Concentration of drug in blood

C brain :

Concentration of drug in brain devoid of blood

C injectate :

Concentration of drug in the injection solution

C plasma :

Concentration of drug in plasma

CLact_efflux :

Active efflux clearance at the BBB (sum of all processes contributing to active efflux)

CLact_uptake :

Active uptake clearance at the BBB (sum of all processes contributing to active uptake)

CLbulk_flow :

Clearance caused by bulk flow of fluid from brain ISF to CSF

CLin :

Influx clearance i.e. the net influx given all transport processes at the BBB

CLmetabolism :

Clearance caused by metabolism in the BBB or brain parenchyma

CLout :

Efflux clearance, i.e., the net efflux given all transport and metabolism processes from the brain ISF

CLpassive :

Passive clearance (permeability surface area product) across the BBB being the same in both directions

CSF:

Cerebrospinal fluid

C tot,brain,ss :

Total brain concentrations at steady state (whole brain minus capillary blood)

C tot,plasma,ss :

Total plasma concentrations at steady state

C u,brainISF :

Concentration of drug in brain ISF

C u,plasma :

Unbound drug concentration in plasma

F :

Blood flow

f u,brain :

Fraction of unbound drug in whole brain homogenate

f u,plasma :

Fraction of unbound drug in plasma

ICF:

Intracellular fluid

ISF:

Interstitial fluid

J in :

Rate of influx to the brain

J out :

Rate of efflux from the brain

K in :

Transfer constant at the BBB (a clearance term)

K out :

Overall loss constant (a clearance term)

K p,brain :

Partition coefficient of total drug between whole brain and plasma

K p,uu,brain :

Partition coefficient of unbound drug between brain ISF and plasma

LC-MS/MS:

Liquid chromatography–tandem mass spectrometry

Mrp1:

Multidrug resistance protein 1

P :

Permeability

PET:

Positron emission tomography

P-gp:

P-glycoprotein

PA:

Permeability surface area product (mL min−1 g brain−1) also denoted PS

Q brain :

Amount of drug in brain parenchyma devoid of blood

Q tot,brain :

Amount of drug in brain parenchyma including capillary blood

V blood :

Physiological volume of blood in brain

V brain :

Effective volume of distribution in the brain

V i :

Effective vascular space in which a compound can be found including endothelial cell binding and accumulation and intravascular volume

V u,brain :

Volume of distribution of unbound drug in the brain

References

  1. Pardridge WM (2005) The blood–brain barrier: bottleneck in brain drug development. NeuroRx 2:3–14

    Article  Google Scholar 

  2. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ (2010) Structure and function of the blood–brain barrier. Neurobiol Dis 37:13–25

    Article  CAS  Google Scholar 

  3. Abbott NJ, Friedman A (2012) Overview and introduction: the blood–brain barrier in health and disease. Epilepsia 53(Suppl 6):1–6

    Article  Google Scholar 

  4. Abbott NJ (2013) Blood–brain barrier structure and function and the challenges for CNS drug delivery. J Inherit Metab Dis 36:437–449

    Article  CAS  Google Scholar 

  5. de Boer AG, Gaillard PJ, Breimer DD (1999) The transference of results between blood–brain barrier cell culture systems. Eur J Pharm Sci 8:1–4

    Article  Google Scholar 

  6. Gumbleton M, Audus KL (2001) 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 90:1681–1698

    Article  CAS  Google Scholar 

  7. Terasaki T, Ohtsuki S, Hori S, Takanaga H, Nakashima E, Hosoya K (2003) New approaches to in vitro models of blood–brain barrier drug transport. Drug Discov Today 8:944–954

    Article  CAS  Google Scholar 

  8. Angelow S, Zeni P, Galla HJ (2004) Usefulness and limitation of primary cultured porcine choroid plexus epithelial cells as an in vitro model to study drug transport at the blood-CSF barrier. Adv Drug Deliv Rev 56:1859–1873

    Article  CAS  Google Scholar 

  9. Prieto P, Blaauboer BJ, de Boer AG, Boveri M, Cecchelli R, Clemedson C, Coecke S, Forsby A, Galla HJ, Garberg P, Greenwood J, Price A, Tahti H (2004) Blood–brain barrier in vitro models and their application in toxicology. The report and recommendations of ECVAM Workshop 49. Altern Lab Anim 32:37–50

    CAS  Google Scholar 

  10. Weksler BB, Subileau EA, Perriere N, Charneau P, Holloway K, Leveque M, Tricoire-Leignel H, Nicotra A, Bourdoulous S, Turowski P, Male DK, Roux F, Greenwood J, Romero IA, Couraud PO (2005) Blood–brain barrier-specific properties of a human adult brain endothelial cell line. FASEB J 19:1872–1874

    CAS  Google Scholar 

  11. Nicolazzo JA, Charman SA, Charman WN (2006) Methods to assess drug permeability across the blood–brain barrier. J Pharm Pharmacol 58:281–293

    Article  CAS  Google Scholar 

  12. Abbott NJ, Dolman DE, Patabendige AK (2008) Assays to predict drug permeation across the blood–brain barrier, and distribution to brain. Curr Drug Metab 9:901–910

    Article  CAS  Google Scholar 

  13. Ribeiro MM, Castanho MA, Serrano I (2010) In vitro blood–brain barrier models–latest advances and therapeutic applications in a chronological perspective. Mini Rev Med Chem 10:262–270

    Article  CAS  Google Scholar 

  14. Lippmann ES, Weidenfeller C, Svendsen CN, Shusta EV (2011) Blood–brain barrier modeling with co-cultured neural progenitor cell-derived astrocytes and neurons. J Neurochem 119:507–520

    Article  CAS  Google Scholar 

  15. Toth A, Veszelka S, Nakagawa S, Niwa M, Deli MA (2011) Patented in vitro blood–brain barrier models in CNS drug discovery. Recent Pat CNS Drug Discov 6:107–118

    Article  CAS  Google Scholar 

  16. Abbott NJ, Dolman DE, Drndarski S, Fredriksson SM (2012) An improved in vitro blood–brain barrier model: rat brain endothelial cells co-cultured with astrocytes. Methods Mol Biol 814:415–430

    Article  CAS  Google Scholar 

  17. Geldenhuys WJ, Allen DD, Bloomquist JR (2012) Novel models for assessing blood–brain barrier drug permeation. Expert Opin Drug Metab Toxicol 8:647–653

    Article  CAS  Google Scholar 

  18. Patabendige A (2012) The value of in vitro models of the blood–brain barrier and their uses. Altern Lab Anim 40:335–338

    CAS  Google Scholar 

  19. Patabendige A, Skinner RA, Abbott NJ (2012) Establishment of a simplified in vitro porcine blood–brain barrier model with high transendothelial electrical resistance. Brain Res 1521:1–15

    Article  Google Scholar 

  20. Daniels BP, Cruz-Orengo L, Pasieka TJ, Couraud PO, Romero IA, Weksler B, Cooper JA, Doering TL, Klein RS (2013) Immortalized human cerebral microvascular endothelial cells maintain the properties of primary cells in an in vitro model of immune migration across the blood brain barrier. J Neurosci Methods 212:173–179

    Article  CAS  Google Scholar 

  21. Lippmann ES, Al-Ahmad A, Palecek SP, Shusta EV (2013) Modeling the blood–brain barrier using stem cell sources. Fluids Barriers CNS 10:2

    Article  Google Scholar 

  22. Weksler B, Romero IA, Couraud PO (2013) The hCMEC/D3 cell line as a model of the human blood brain barrier. Fluids Barriers CNS 10:16

    Article  Google Scholar 

  23. Bonate PL (1995) Animal models for studying transport across the blood–brain barrier. J Neurosci Methods 56:1–15

    Article  CAS  Google Scholar 

  24. Smith QR (1996) Brain perfusion systems for studies of drug uptake and metabolism in the central nervous system. Pharm Biotechnol 8:285–307

    Article  CAS  Google Scholar 

  25. Elmquist WF, Sawchuk RJ (1997) Application of microdialysis in pharmacokinetic studies. Pharm Res 14:267–288

    Article  CAS  Google Scholar 

  26. Hammarlund-Udenaes M (2000) The use of microdialysis in CNS drug delivery studies. Pharmacokinetic perspectives and results with analgesics and antiepileptics. Adv Drug Deliv Rev 45:283–294

    Article  CAS  Google Scholar 

  27. Bickel U (2005) How to measure drug transport across the blood–brain barrier. NeuroRx 2:15–26

    Article  Google Scholar 

  28. Mensch J, Oyarzabal J, Mackie C, Augustijns P (2009) In vivo, in vitro and in silico methods for small molecule transfer across the BBB. J Pharm Sci 98:4429–4468

    Article  CAS  Google Scholar 

  29. Jeffrey P, Summerfield S (2010) Assessment of the blood–brain barrier in CNS drug discovery. Neurobiol Dis 37:33–37

    Article  CAS  Google Scholar 

  30. Bostrom E, Simonsson US, Hammarlund-Udenaes M (2006) In vivo blood–brain barrier transport of oxycodone in the rat: indications for active influx and implications for pharmacokinetics/pharmacodynamics. Drug Metab Dispos 34:1624–1631

    Article  Google Scholar 

  31. Sadiq MW, Borgs A, Okura T, Shimomura K, Kato S, Deguchi Y, Jansson B, Bjorkman S, Terasaki T, Hammarlund-Udenaes M (2011) Diphenhydramine active uptake at the blood–brain barrier and its interaction with oxycodone in vitro and in vivo. J Pharm Sci 100:3912–3923

    Article  CAS  Google Scholar 

  32. Levin VA, Fenstermacher JD, Patlak CS (1970) Sucrose and inulin space measurements of cerebral cortex in four mammalian species. Am J Physiol 219:1528–1533

    CAS  Google Scholar 

  33. Watson J, Wright S, Lucas A, Clarke KL, Viggers J, Cheetham S, Jeffrey P, Porter R, Read KD (2009) Receptor occupancy and brain free fraction. Drug Metab Dispos 37:753–760

    Article  CAS  Google Scholar 

  34. Friden M, Ducrozet F, Middleton B, Antonsson M, Bredberg U, Hammarlund-Udenaes M (2009) Development of a high-throughput brain slice method for studying drug distribution in the central nervous system. Drug Metab Dispos 37:1226–1233

    Article  CAS  Google Scholar 

  35. Friden M, Winiwarter S, Jerndal G, Bengtsson O, Wan H, Bredberg U, Hammarlund-Udenaes M, Antonsson M (2009) 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 52:6233–6243

    Article  CAS  Google Scholar 

  36. Gupta A, Chatelain P, Massingham R, Jonsson EN, Hammarlund-Udenaes M (2006) Brain distribution of cetirizine enantiomers: comparison of three different tissue-to-plasma partition coefficients: K(p), K(p, u), and K(p, uu). Drug Metab Dispos 34:318–323

    Article  CAS  Google Scholar 

  37. Hammarlund-Udenaes M, Friden M, Syvanen S, Gupta A (2008) On the rate and extent of drug delivery to the brain. Pharm Res 25:1737–1750

    Article  CAS  Google Scholar 

  38. Cserr HF, Cooper DN, Milhorat TH (1977) Flow of cerebral interstitial fluid as indicated by the removal of extracellular markers from rat caudate nucleus. Exp Eye Res 25(Suppl):461–473

    Article  Google Scholar 

  39. Nicholson C, Sykova E (1998) Extracellular space structure revealed by diffusion analysis. Trends Neurosci 21:207–215

    Article  CAS  Google Scholar 

  40. Tunblad K, Jonsson EN, Hammarlund-Udenaes M (2003) Morphine blood–brain barrier transport is influenced by probenecid co-administration. Pharm Res 20:618–623

    Article  CAS  Google Scholar 

  41. Dagenais C, Graff CL, Pollack GM (2004) Variable modulation of opioid brain uptake by P-glycoprotein in mice. Biochem Pharmacol 67:269–276

    Article  CAS  Google Scholar 

  42. Tunblad K, Hammarlund-Udenaes M, Jonsson EN (2005) Influence of probenecid on the delivery of morphine-6-glucuronide to the brain. Eur J Pharm Sci 24:49–57

    Article  CAS  Google Scholar 

  43. Ohno K, Pettigrew KD, Rapoport SI (1978) Lower limits of cerebrovascular permeability to nonelectrolytes in the conscious rat. Am J Physiol 235:H299–H307

    CAS  Google Scholar 

  44. Patlak CS, Blasberg RG, Fenstermacher JD (1983) Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metabol 3:1–7

    Article  CAS  Google Scholar 

  45. Takasato Y, Rapoport SI, Smith QR (1984) An in situ brain perfusion technique to study cerebrovascular transport in the rat. Am J Physiol 247:H484–H493

    CAS  Google Scholar 

  46. Smith QR (1989) Quantitation of blood–brain barrier permeability. In: Neuwelt EA (ed) Implications of the blood–brain barrier and its manipulation, vol 1. Plenum, New York, pp 85–118

    Chapter  Google Scholar 

  47. Smith QR (2003) A review of blood–brain barrier transport techniques. Methods Mol Med 89:193–208

    CAS  Google Scholar 

  48. Blasberg RG, Patlak CS, Fenstermacher JD (1983) Selection of experimental conditions for the accurate determination of blood–brain transfer constants from single-time experiments: a theoretical analysis. J Cereb Blood Flow Metab 3:215–225

    Article  CAS  Google Scholar 

  49. Renkin EM (1959) Transport of potassium-42 from blood to tissue in isolated mammalian skeletal muscles. Am J Physiol 197:1205–1210

    CAS  Google Scholar 

  50. Crone C (1963) The permeability of capillaries in various organs as determined by Use of the “indicator diffusion” method. Acta Physiol Scand 58:292–305

    Article  CAS  Google Scholar 

  51. Friden M, Bergstrom F, Wan H, Rehngren M, Ahlin G, Hammarlund-Udenaes M, Bredberg U (2011) 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 39:353–362

    Article  CAS  Google Scholar 

  52. Pardridge WM (1995) Transport of small molecules through the blood–brain barrier: biology and methodology. Adv Drug Deliv Rev 15:5–36

    Article  CAS  Google Scholar 

  53. Hammarlund-Udenaes M, Bredberg U, Friden M (2009) Methodologies to assess brain drug delivery in lead optimization. Curr Top Med Chem 9:148–162

    Article  CAS  Google Scholar 

  54. Oldendorf WH (1970) Measurement of brain uptake of radiolabeled substances using a tritiated water internal standard. Brain Res 24:372–376

    Article  CAS  Google Scholar 

  55. Smith QR, Allen DD (2003) In situ brain perfusion technique. Methods Mol Med 89:209–218

    Google Scholar 

  56. Dagenais C, Rousselle C, Pollack GM, Scherrmann JM (2000) Development of an in situ mouse brain perfusion model and its application to mdr1a P-glycoprotein-deficient mice. J Cereb Blood Flow Metab 20:381–386

    Article  CAS  Google Scholar 

  57. Murakami H, Takanaga H, Matsuo H, Ohtani H, Sawada Y (2000) Comparison of blood–brain barrier permeability in mice and rats using in situ brain perfusion technique. Am J Physiol Heart Circ Physiol 279:H1022–H1028

    CAS  Google Scholar 

  58. Cisternino S, Rousselle C, Dagenais C, Scherrmann JM (2001) Screening of multidrug-resistance sensitive drugs by in situ brain perfusion in P-glycoprotein-deficient mice. Pharm Res 18:183–190

    Article  CAS  Google Scholar 

  59. Kakee A, Terasaki T, Sugiyama Y (1996) Brain efflux index as a novel method of analyzing efflux transport at the blood–brain barrier. J Pharmacol Exp Ther 277:1550–1559

    CAS  Google Scholar 

  60. Kakee A, Terasaki T, Sugiyama Y (1997) Selective brain to blood efflux transport of para-aminohippuric acid across the blood–brain barrier: in vivo evidence by use of the brain efflux index method. J Pharmacol Exp Ther 283:1018–1025

    CAS  Google Scholar 

  61. Ohtsuki S, Asaba H, Takanaga H, Deguchi T, Hosoya K, Otagiri M, Terasaki T (2002) 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 83:57–66

    Article  CAS  Google Scholar 

  62. de Lange EC, Danhof M, de Boer AG, Breimer DD (1997) Methodological considerations of intracerebral microdialysis in pharmacokinetic studies on drug transport across the blood–brain barrier. Brain Res Brain Res Rev 25:27–49

    Article  Google Scholar 

  63. de Lange EC, de Boer AG, Breimer DD (2000) Methodological issues in microdialysis sampling for pharmacokinetic studies. Adv Drug Deliv Rev 45:125–148

    Article  Google Scholar 

  64. Sawchuk RJ, Elmquist WF (2000) Microdialysis in the study of drug transporters in the CNS. Adv Drug Deliv Rev 45:295–307

    Article  CAS  Google Scholar 

  65. de Lange EC, Ravenstijn PG, Groenendaal D, van Steeg TJ (2005) Toward the prediction of CNS drug-effect profiles in physiological and pathological conditions using microdialysis and mechanism-based pharmacokinetic-pharmacodynamic modeling. AAPS J 7:E532–E543

    Article  Google Scholar 

  66. Chaurasia CS, Muller M, Bashaw ED, Benfeldt E, Bolinder J, Bullock R, Bungay PM, DeLange EC, Derendorf H, Elmquist WF, Hammarlund-Udenaes M, Joukhadar C, Kellogg DL Jr, Lunte CE, Nordstrom CH, Rollema H, Sawchuk RJ, Cheung BW, Shah VP, Stahle L, Ungerstedt U, Welty DF, Yeo H (2007) AAPS-FDA workshop white paper: microdialysis principles, application and regulatory perspectives. Pharm Res 24:1014–1025

    Article  CAS  Google Scholar 

  67. Tunblad K, Hammarlund-Udenaes M, Jonsson EN (2004) An integrated model for the analysis of pharmacokinetic data from microdialysis experiments. Pharm Res 21:1698–1707

    Article  CAS  Google Scholar 

  68. Bostrom E, Hammarlund-Udenaes M, Simonsson US (2008) Blood–brain barrier transport helps to explain discrepancies in in vivo potency between oxycodone and morphine. Anesthesiology 108:495–505

    Article  Google Scholar 

  69. de Lange EC, Danhof M, Zurcher C, de Boer AG, Breimer DD (1995) Repeated microdialysis perfusions: periprobe tissue reactions and BBB permeability. Brain Res 702:261–265

    Article  Google Scholar 

  70. Mou X, Lennartz MR, Loegering DJ, Stenken JA (2010) Long-term calibration considerations during subcutaneous microdialysis sampling in mobile rats. Biomaterials 31:4530–4539

    Article  CAS  Google Scholar 

  71. Bouw MR, Hammarlund-Udenaes M (1998) Methodological aspects of the use of a calibrator in in vivo microdialysis-further development of the retrodialysis method. Pharm Res 15:1673–1679

    Article  CAS  Google Scholar 

  72. Olson R, Justice J (1993) Quantitative microdialysis under transient conditions. Anal Chem 65:1017–1022

    Article  CAS  Google Scholar 

  73. Bengtsson J, Bostrom E, Hammarlund-Udenaes M (2008) The use of a deuterated calibrator for in vivo recovery estimations in microdialysis studies. J Pharm Sci 97:3433–3441

    Article  CAS  Google Scholar 

  74. Dahlin AP, Hjort K, Hillered L, Sjodin MO, Bergquist J, Wetterhall M (2012) Multiplexed quantification of proteins adsorbed to surface-modified and non-modified microdialysis membranes. Anal Bioanal Chem 402:2057–2067

    Article  CAS  Google Scholar 

  75. Gazzin S, Strazielle N, Schmitt C, Fevre-Montange M, Ostrow JD, Tiribelli C, Ghersi-Egea JF (2008) Differential expression of the multidrug resistance-related proteins ABCb1 and ABCc1 between blood–brain interfaces. J Comp Neurol 510:497–507

    Article  CAS  Google Scholar 

  76. Westerhout J, Ploeger B, Smeets J, Danhof M, de Lange EC (2012) Physiologically based pharmacokinetic modeling to investigate regional brain distribution kinetics in rats. AAPS J 14:543–553

    Article  CAS  Google Scholar 

  77. de Lange EC, Danhof M (2002) 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 41:691–703

    Article  Google Scholar 

  78. Shen DD, Artru AA, Adkison KK (2004) Principles and applicability of CSF sampling for the assessment of CNS drug delivery and pharmacodynamics. Adv Drug Deliv Rev 56:1825–1857

    Article  CAS  Google Scholar 

  79. Lin JH (2008) CSF as a surrogate for assessing CNS exposure: an industrial perspective. Curr Drug Metab 9:46–59

    Article  CAS  Google Scholar 

  80. Westerhout J, Danhof M, De Lange EC (2011) Preclinical prediction of human brain target site concentrations: considerations in extrapolating to the clinical setting. J Pharm Sci 100:3577–3593

    Article  CAS  Google Scholar 

  81. Portnow LH, Vaillancourt DE, Okun MS (2013) The history of cerebral PET scanning: from physiology to cutting-edge technology. Neurology 80:952–956

    Article  Google Scholar 

  82. Syvanen S, Hammarlund-Udenaes M (2010) Using PET studies of P-gp function to elucidate mechanisms underlying the disposition of drugs. Curr Top Med Chem 10(17):1799–1809

    Article  Google Scholar 

  83. Liu X, Ding X, Deshmukh G, Liederer BM, Hop CE (2012) Use of the cassette-dosing approach to assess brain penetration in drug discovery. Drug Metab Dispos 40:963–969

    Article  CAS  Google Scholar 

  84. Friden M, Gupta A, Antonsson M, Bredberg U, Hammarlund-Udenaes M (2007) In vitro methods for estimating unbound drug concentrations in the brain interstitial and intracellular fluids. Drug Metab Dispos 35:1711–1719

    Article  CAS  Google Scholar 

  85. Loryan I, Friden M, Hammarlund-Udenaes M (2013) The brain slice method for studying drug distribution in the CNS. Fluids Barriers CNS 10:6

    Article  Google Scholar 

  86. Friden M, Ljungqvist H, Middleton B, Bredberg U, Hammarlund-Udenaes M (2010) Improved measurement of drug exposure in the brain using drug-specific correction for residual blood. J Cereb Blood Flow Metab 30:150–161

    Article  CAS  Google Scholar 

  87. Kalvass JC, Maurer TS (2002) Influence of nonspecific brain and plasma binding on CNS exposure: implications for rational drug discovery. Biopharm Drug Dispos 23:327–338

    Article  CAS  Google Scholar 

  88. Mano Y, Higuchi S, Kamimura H (2002) Investigation of the high partition of YM992, a novel antidepressant, in rat brain – in vitro and in vivo evidence for the high binding in brain and the high permeability at the BBB. Biopharm Drug Dispos 23:351–360

    Article  CAS  Google Scholar 

  89. Di L, Umland JP, Chang G, Huang Y, Lin Z, Scott DO, Troutman MD, Liston TE (2011) Species independence in brain tissue binding using brain homogenates. Drug Metab Dispos 39:1270–1277

    Article  CAS  Google Scholar 

  90. Reese TS, Karnovsky MJ (1967) Fine structural localization of a blood–brain barrier to exogenous peroxidase. J Cell Biol 34:207–217

    Article  CAS  Google Scholar 

  91. Oldendorf WH, Hyman S, Braun L, Oldendorf SZ (1972) Blood–brain barrier: penetration of morphine, codeine, heroin, and methadone after carotid injection. Science 178:984–986

    Article  CAS  Google Scholar 

  92. Hosoya K, Ohtsuki S, Terasaki T (2002) Recent advances in the brain-to-blood efflux transport across the blood–brain barrier. Int J Pharm 248:15–29

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Translational PKPD Group, Department of Pharmaceutical Biosciences, Uppsala University, 591, 751 24, Uppsala, Sweden

    Margareta Hammarlund-Udenaes

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  1. Margareta Hammarlund-Udenaes
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Correspondence to Margareta Hammarlund-Udenaes .

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Editors and Affiliations

  1. Institut für Pharmazie und Molekulare Biotechnologie, Universität Heidelberg, Heidelberg, Baden-Württemberg, Germany

    Gert Fricker

  2. Dept. for Pharmaceutical Technology and Pharmacology, Institute für Pharmacy and Molecular Biotechnology, Heidelberg, Germany

    Melanie Ott

  3. Dept. for Pharmaceutical Technology and Pharmacology, Institute für Pharmacy and Molecular Biotechnology, Heidelberg, Germany

    Anne Mahringer

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Hammarlund-Udenaes, M. (2013). In Vivo Approaches to Assessing the Blood–Brain Barrier. In: Fricker, G., Ott, M., Mahringer, A. (eds) The Blood Brain Barrier (BBB). Topics in Medicinal Chemistry, vol 10. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7355_2013_27

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