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Because of the properties of the blood– brain barrier, researchers accept a high likelihood of failure when developing drugs for brain delivery

On the rate and extent of drug delivery to the brain.

Pharmaceutical research, no. 8 (2008): 1737-1750

Cited by: 303|Views14
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Abstract

To define and differentiate relevant aspects of blood-brain barrier transport and distribution in order to aid research methodology in brain drug delivery. Pharmacokinetic parameters relative to the rate and extent of brain drug delivery are described and illustrated with relevant data, with special emphasis on the unbound, pharmacologica...More

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Introduction
  • For central drug effects to occur, the drug must first be delivered to the brain. Because of the properties of the blood– brain barrier (BBB), researchers accept a high likelihood of failure when developing drugs for brain delivery [1,2].
  • Confusion remains, and an intense debate is currently raging regarding how to interpret the results obtained and which methods to use to select candidates for central nervous system (CNS) action [14,15,16].
  • The lack of success in this respect to date might be due to a lack of common understanding regarding which processes and properties are most relevant to successful brain drug delivery.
  • In order to interpret in vivo results correctly, the various processes
Highlights
  • For central drug effects to occur, the drug must first be delivered to the brain
  • Because of the properties of the blood– brain barrier (BBB), researchers accept a high likelihood of failure when developing drugs for brain delivery [1,2]
  • The lack of success in this respect to date might be due to a lack of common understanding regarding which processes and properties are most relevant to successful brain drug delivery
  • The difference in volume between the drugs can be interpreted to mean that morphine distributes into the cells while M6G is confined more to the interstitial fluid (ISF) of the brain
  • The parameters needed for a full description of delivery of drugs to the brain are 1) the permeability clearance, 2) the extent of equilibrium across the BBB, described by the ratio of unbound concentrations in brain ISF to those in blood (Kp,uu), and 3) the intra-brain distribution volume (Vu,brain)
  • Relevant in vivo estimations of drug delivery to the brain can be fully described using three parameters: CLin to describe the permeability clearance into the brain, Kp,uu to describe the ratio of unbound drug in brain to that in blood, and Vu,brain to describe the intra-brain distribution
Methods
  • Microdialysis In situ brain perfusion In situ brain perfusion In situ brain perfusion Microdialysis i.v. injection technique Microdialysis Microdialysis In situ brain perfusion Microdialysis i.v. injection technique i.v. injection technique Microdialysis Microdialysis In situ brain perfusion Microdialysis i.v. injection technique Species

    Values are given as ± SD or (RSE%).

    peptide, the selective delta opioid receptor agonist DPDPE has a higher influx clearance than M3G.
  • The unbound concentration ratio Kp,uu is similar at about 0.29 (Fig. 4, Table III).
  • How can this be, and what does it mean regarding the pharmacodynamics of morphine and M6G?
  • The 10-fold difference in influx clearance between morphine and M6G will not correlate with the similar extent of equilibration across the BBB of morphine and M6G
Results
  • EXPERIMENTAL FINDINGS IN RELATION TO BASIC CONCEPTS

    The purpose of this section is to illustrate the consequences of different types of measurements on interpretation of the results.
  • Most of the experimental results are from studies of opioids, as this group of drugs has been studied extensively using several of the brain transport methods reviewed here.
  • The potential change in brain concentrations due to drug interactions at the BBB, or interaction potential, can be measured quantitatively.
  • If no active transport takes place at the BBB, BBB permeability clearances of the various opioids span almost a 20,000-fold range (Table II), which is nearly as wide as that reported for drugs in general [80].
Conclusion
  • This paper defines the factors of importance for determining and predicting drug delivery to the brain.
  • The parameters needed for a full description of delivery of drugs to the brain are 1) the permeability clearance, 2) the extent of equilibrium across the BBB, described by the ratio of unbound concentrations in brain ISF to those in blood (Kp,uu), and 3) the intra-brain distribution volume (Vu,brain).
  • It is hoped that this paper will provide inspiration for evidence-based consideration of the choice of methods for determining successful brain penetration
Tables
  • Table1: Collated Information from the Literature on Physiological Values Relevant to Drug Transport and Distribution in the Rat Brain
  • Table2: Permeability Clearances of Drugs at the Blood–Brain Barrier in Decreasing Order, Determined Using Different Methods
  • Table3: Extent of Equilibration Across the BBB and Intra-Brain Distribution of Drugs in the Rat
Download tables as Excel
Reference
  • The size of the interaction potential is given by the inverse of Kp,uu. If no active transport takes place at the BBB, BBB permeability clearances of the various opioids span almost a 20,000-fold range (Table II), which is nearly as wide as that reported for drugs in general (80). Results using microdialysis and in situ methods based on total brain concentrations seem to be similar for the few drugs for which both methods have been used. Various conclusions can be drawn from these data. Oxycodone has the highest permeability clearance rate (1910 μl ml−1g brain−1) while M3G has the lowest (0.11 μl ml−1 g brain−1). Most opioids have higher permeability clearances than morphine. Although it is a
    Google ScholarFindings
  • 1. M. R. Feng. Assessment of blood–brain barrier penetration: in silico, in vitro and in vivo. Current Drug Metabolism 3:647–657 (2002).
    Google ScholarLocate open access versionFindings
  • 2. W. M. Pardridge. The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2:3–14 (2005).
    Google ScholarLocate open access versionFindings
  • 3. S. Becker, and X. Liu. Evaluation of the utility of brain slice methods to study brain penetration. Drug. Metab. Dispos. 34:855–861 (2006).
    Google ScholarLocate open access versionFindings
  • 4. M. Fridén, A. Gupta, M. Antonsson, U. Bredberg, and M. Hammarlund-Udenaes. In vitro methods for estimating unbound drug concentrations in the brain interstitial and intracellular fluids. Drug. Metab. Dispos. 35:1711–1719 (2007).
    Google ScholarLocate open access versionFindings
  • 5. X. Liu, B. J. Smith, C. Chen, E. Callegari, S. L. Becker, X. Chen, J. Cianfrogna, A. C. Doran, S. D. Doran, J. P. Gibbs, N. Hosea, J. Liu, F. R. Nelson, M. A. Szewc, and J. Van Deusen. 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. 313:1254–1262 (2005).
    Google ScholarLocate open access versionFindings
  • 6. X. Liu and C. Chen. Strategies to optimize brain penetration in drug discovery. Curr. Opin. Drug Discov. Dev. 8:505–512 (2005).
    Google ScholarLocate open access versionFindings
  • 7. X. Liu, B. J. Smith, C. Chen, E. Callegari, S. L. Becker, X. Chen, J. Cianfrogna, A. C. Doran, S. D. Doran, J. P. Gibbs, N. Hosea, J. Liu, F. R. Nelson, M. A. Szewc, and J. Van Deusen. Evaluation Of cerebrospinal fluid concentration and plasma free concentration as a surrogate measurement for brain free concentration. Drug. Metab. Dispos. (2006).
    Google ScholarLocate open access versionFindings
  • 8. W. M. Pardridge. The blood–brain barrier and neurotherapeutics. NeuroRx 2:1–2 (2005).
    Google ScholarLocate open access versionFindings
  • 9. D. J. Begley. Delivery of therapeutic agents to the central nervous system: the problems and the possibilities. Pharmacol. Ther. 104:29–45 (2004).
    Google ScholarLocate open access versionFindings
  • 10. U. Bickel. How to measure drug transport across the blood– brain barrier. NeuroRx 2:15–26 (2005).
    Google ScholarLocate open access versionFindings
  • 11. P. Garberg, M. Ball, N. Borg, R. Cecchelli, L. Fenart, R. D. Hurst, T. Lindmark, A. Mabondzo, J. E. Nilsson, T. J. Raub, D. Stanimirovic, T. Terasaki, J. O. Oberg, and T. Osterberg. In vitro models for the blood–brain barrier. Toxicol. in Vitro 19:299–334 (2005).
    Google ScholarFindings
  • 12. S. G. Summerfield, K. Read, D. J. Begley, T. Obradovic, I. J. Hidalgo, S. Coggon, A. V. Lewis, R. A. Porter, and P. Jeffrey. Central nervous system drug disposition: the relationship between in situ brain permeability and brain free fraction. J. Pharmacol. Exp. Ther. 322:205–213 (2007).
    Google ScholarLocate open access versionFindings
  • 13. S. G. Summerfield, A. J. Stevens, L. Cutler, M. del Carmen Osuna, B. Hammond, S. P. Tang, A. Hersey, D. J. Spalding, and P. Jeffrey. Improving the in vitro prediction of in vivo central nervous system penetration: integrating permeability, Pglycoprotein efflux, and free fractions in blood and brain. J. Pharmacol. Exp. Ther. 316:1282–1290 (2006).
    Google ScholarLocate open access versionFindings
  • 14. I. Martin. Prediction of blood–brain barrier penetration: are we missing the point? [see comment] [comment]. Drug Discov. Today 9:161–162 (2004).
    Google ScholarLocate open access versionFindings
  • 15. W. M. Pardridge. Log(BB), PS products and in silico models of drug brain penetration. [comment]. Drug Discov. Today 9:392– 393 (2004).
    Google ScholarLocate open access versionFindings
  • 16. L. Cucullo, B. Aumayr, E. Rapp, and D. Janigro. Drug delivery and in vitro models of the blood–brain barrier. Curr. Opin. Drug Discov. Dev. 8:89–99 (2005).
    Google ScholarLocate open access versionFindings
  • 17. M. Hammarlund-Udenaes. The use of microdialysis in CNS drug delivery studies. Pharmacokinetic perspectives and results with analgesics and antiepileptics. Adv. Drug Deliv. Rev. 45:283–294 (2000).
    Google ScholarLocate open access versionFindings
  • 18. M. Hammarlund-Udenaes, L. K. Paalzow, and E. C. de Lange. Drug equilibration across the blood–brain barrier-pharmacokinetic considerations based on the microdialysis method. Pharm. Res. 14:128–134 (1997).
    Google ScholarLocate open access versionFindings
  • 19. D. J. Begley. ABC transporters and the blood–brain barrier. Curr. Pharm. Des. 10:1295–1312 (2004).
    Google ScholarLocate open access versionFindings
  • 20. W. Loscher and H. Potschka. Blood–brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx 2:86– 98 (2005).
    Google ScholarLocate open access versionFindings
  • 21. H. Kusuhara and Y. Sugiyama. Active efflux across the blood– brain barrier: role of the solute carrier family. NeuroRx 2:73–85 (2005).
    Google ScholarLocate open access versionFindings
  • 22. A. Tsuji. Small molecular drug transfer across the blood–brain barrier via carrier-mediated transport systems. NeuroRx 2:54– 62 (2005).
    Google ScholarLocate open access versionFindings
  • 23. J. M. Scherrmann. Expression and function of multidrug resistance transporters at the blood–brain barriers. Expert Opin. Drug Metab. Toxicol. 1:233–246 (2005).
    Google ScholarLocate open access versionFindings
  • 24. S. Dallas, D. S. Miller, and R. Bendayan. Multidrug resistanceassociated proteins: expression and function in the central nervous system. Pharmacol. Rev. 58:140–161 (2006).
    Google ScholarLocate open access versionFindings
  • 25. A. Tsuji, T. Terasaki, Y. Takabatake, Y. Tenda, I. Tamai, T. Yamashima, S. Moritani, T. Tsuruo, and J. Yamashita. Pglycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells. Life Sci. 51:1427–1437 (1992).
    Google ScholarLocate open access versionFindings
  • 26. H. C. Cooray, C. G. Blackmore, L. Maskell, and M. A. Barrand. Localisation of breast cancer resistance protein in microvessel endothelium of human brain. NeuroReport 13:2059–2063 (2002).
    Google ScholarLocate open access versionFindings
  • 27. S. Mori, H. Takanaga, S. Ohtsuki, T. Deguchi, Y. S. Kang, K. Hosoya, and T. Terasaki. 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. 23:432–440 (2003).
    Google ScholarLocate open access versionFindings
  • 28. B. Gao, B. Stieger, B. Noe, J. M. Fritschy, and P. J. Meier. Localization of the organic anion transporting polypeptide 2 (Oatp2) in capillary endothelium and choroid plexus epithelium of rat brain. J. Histochem. Cytochem. 47:1255–1264 (1999).
    Google ScholarLocate open access versionFindings
  • 29. C. Nicholson, and E. Sykova. Extracellular space structure revealed by diffusion analysis. [see comment]. Trends Neurosci. 21:207–215 (1998).
    Google ScholarLocate open access versionFindings
  • 30. C. Nicholson, J. M. Phillips, and A. R. Gardner-Medwin. Diffusion from an iontophoretic point source in the brain: role of tortuosity and volume fraction. Brain Res. 169:580–584 (1979).
    Google ScholarLocate open access versionFindings
  • 31. H. F. Cserr, D. N. Cooper, P. K. Suri, and C. S. Patlak. Efflux of radiolabeled polyethylene glycols and albumin from rat brain. Am. J. Physiol. 240:F319–F328 (1981).
    Google ScholarLocate open access versionFindings
  • 32. I. Szentistvanyi, C. S. Patlak, R. A. Ellis, and H. F. Cserr. Drainage of interstitial fluid from different regions of rat brain. Am. J. Physiol. 246:F835–F844 (1984).
    Google ScholarLocate open access versionFindings
  • 33. N. J. Abbott. Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem. Int. 45:545–552 (2004).
    Google ScholarLocate open access versionFindings
  • 34. T. Ooie, T. Terasaki, H. Suzuki, and Y. Sugiyama. Kinetic evidence for active efflux transport across the blood–brain barrier of quinolone antibiotics. J. Pharmacol. Exp. Ther. 283:293–304 (1997).
    Google ScholarLocate open access versionFindings
  • 35. E. C. de Lange, and M. Danhof. 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 (2002).
    Google ScholarLocate open access versionFindings
  • 36. D. D. Shen, A. A. Artru, and K. K. Adkison. Principles and applicability of CSF sampling for the assessment of CNS drug delivery and pharmacodynamics. Adv. Drug Deliv. Rev. 56:1825–1857 (2004).
    Google ScholarLocate open access versionFindings
  • 37. F. Stain-Texier, G. Boschi, P. Sandouk, and J. M. Scherrmann. Elevated concentrations of morphine 6-beta-D-glucuronide in brain extracellular fluid despite low blood-brain barrier permeability. Br. J. Pharmacol. 128:917–924 (1999).
    Google ScholarLocate open access versionFindings
  • 38. R. K. Dubey, C. B. McAllister, M. Inoue, and G. R. Wilkinson. Plasma binding and transport of diazepam across the blood– brain barrier. No evidence for in vivo enhanced dissociation. J. Clin. Invest. 84:1155–1159 (1989).
    Google ScholarLocate open access versionFindings
  • 39. P. M. Klockowski, and G. Levy. Kinetics of drug action in disease states. XXIV. Pharmacodynamics of diazepam and its active metabolites in rats. J. Pharmacol. Exp. Ther. 244:912–918 (1988).
    Google ScholarLocate open access versionFindings
  • 40. R. Xie, M. R. Bouw, and M. Hammarlund-Udenaes. Modelling of the blood-brain barrier transport of morphine-3-glucuronide studied using microdialysis in the rat: involvement of probenecidsensitive transport. Br. J. Pharmacol. 131:1784–1792 (2000).
    Google ScholarLocate open access versionFindings
  • 41. P. L. Golden and G. M. Pollack. Rationale for influx enhancement versus efflux blockade to increase drug exposure to the brain. Biopharm. Drug Dispos. 19:263–272 (1998).
    Google ScholarLocate open access versionFindings
  • 42. S. Syvänen, R. Xie, S. Sahin, and M. Hammarlund-Udenaes. Pharmacokinetic consequences of active drug efflux at the blood–brain barrier. Pharm. Res. (2006).
    Google ScholarLocate open access versionFindings
  • 43. C. F. Higgins and M. M. Gottesman. Is the multidrug transporter a flippase? Trends Biochem. Sci. 17:18–21 (1992).
    Google ScholarLocate open access versionFindings
  • 44. W. D. Stein, C. Cardarelli, I. Pastan, and M. M. Gottesman. Kinetic evidence suggesting that the multidrug transporter differentially handles influx and efflux of its substrates. Mol. Pharmacol. 45:763–772 (1994).
    Google ScholarLocate open access versionFindings
  • 45. F. J. Sharom. The P-glycoprotein efflux pump: how does it transport drugs? [see comment]. J Memb. Biol. 160:161–175 (1997).
    Google ScholarLocate open access versionFindings
  • 46. C. F. Higgins and K. J. Linton. The ATP switch model for ABC transporters. Nat. Struct. Mol. Biol. 11:918–926 (2004).
    Google ScholarLocate open access versionFindings
  • 47. S. Mori, S. Ohtsuki, H. Takanaga, T. Kikkawa, Y. S. Kang, and T. Terasaki. Organic anion transporter 3 is involved in the brainto-blood efflux transport of thiopurine nucleobase analogs. J. Neurochem. 90:931–941 (2004).
    Google ScholarLocate open access versionFindings
  • 48. W. H. Oldendorf. Measurement of brain uptake of radiolabeled substances using a tritiated water internal standard. Brain Res. 24:372–376 (1970).
    Google ScholarLocate open access versionFindings
  • 49. Y. Takasato, S. I. Rapoport, and Q. R. Smith. An in situ brain perfusion technique to study cerebrovascular transport in the rat. Am. J. Physiol. 247:H484–H493 (1984).
    Google ScholarLocate open access versionFindings
  • 50. C. Dagenais, C. Rousselle, G. M. Pollack, and J. M. Scherrmann. 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 (2000).
    Google ScholarLocate open access versionFindings
  • 51. K. Ohno, K. D. Pettigrew, and S. I. Rapoport. Lower limits of cerebrovascular permeability to nonelectrolytes in the conscious rat. Am. J. Physiol. 235:H299–H307 (1978).
    Google ScholarLocate open access versionFindings
  • 52. C. S. Patlak, R. G. Blasberg, and J. D. Fenstermacher. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J. Cereb. Blood Flow Metab. 3:1–7 (1983).
    Google ScholarLocate open access versionFindings
  • 53. H. Benveniste and P. C. Huttemeier. Microdialysis—theory and application. Prog. Neurobiol. 35:195–215 (1990).
    Google ScholarLocate open access versionFindings
  • 54. E. C. de Lange, M. Danhof, A. G. de Boer, and D. D. Breimer. Methodological considerations of intracerebral microdialysis in pharmacokinetic studies on drug transport across the blood– brain barrier. Brain Res. Brain Res. Rev. 25:27–49 (1997).
    Google ScholarLocate open access versionFindings
  • 55. E. C. de Lange, A. G. de Boer, and D. D. Breimer. Methodological issues in microdialysis sampling for pharmacokinetic studies. Adv. Drug Deliv. Rev. 45:125–148 (2000).
    Google ScholarLocate open access versionFindings
  • 56. E. C. de Lange, B. A. de Boer, and D. D. Breimer. Microdialysis for pharmacokinetic analysis of drug transport to the brain. Adv. Drug Deliv. Rev. 36:211–227 (1999).
    Google ScholarLocate open access versionFindings
  • 57. W. F. Elmquist and R. J. Sawchuk. Application of microdialysis in pharmacokinetic studies. Pharm. Res. 14:267–288 (1997).
    Google ScholarLocate open access versionFindings
  • 58. J. Kehr. A survey on quantitative microdialysis: theoretical models and practical implications. J. Neurosci. Methods 48:251– 261 (1993).
    Google ScholarLocate open access versionFindings
  • 59. Q. R. Smith. A review of blood–brain barrier transport techniques. Methods in Molecular Medicine 89:193–208 (2003).
    Google ScholarLocate open access versionFindings
  • 60. W. M. Pardridge. Introduction to the Blood–Brain Barrier, Cambridge University Press, Cambridge, 1998.
    Google ScholarFindings
  • 61. A. Kakee, T. Terasaki, and Y. Sugiyama. Brain efflux index as a novel method of analyzing efflux transport at the blood–brain barrier. J. Pharmacol. Exp. Ther. 277:1550–1559 (1996).
    Google ScholarLocate open access versionFindings
  • 62. Y. Wang and R. J. Sawchuk. Zidovudine transport in the rabbit brain during intravenous and intracerebroventricular infusion. J. Pharm. Sci. 84:871–876 (1995).
    Google ScholarLocate open access versionFindings
  • 63. Y. Wang and D. F. Welty. The simultaneous estimation of the influx and efflux blood–brain barrier permeabilities of gabapentin using a microdialysis-pharmacokinetic approach. Pharm. Res. 13:398–403 (1996).
    Google ScholarLocate open access versionFindings
  • 64. Y. Deguchi, K. Nozawa, S. Yamada, Y. Yokoyama, and R. Kimura. Quantitative evaluation of brain distribution and blood–brain barrier efflux transport of probenecid in rats by microdialysis: possible involvement of the monocarboxylic acid transport system. J. Pharmacol. Exp. Ther. 280:551–560 (1997).
    Google ScholarLocate open access versionFindings
  • 65. Y. Deguchi, K. Inabe, K. Tomiyasu, K. Nozawa, S. Yamada, and R. Kimura. Study on brain interstitial fluid distribution and blood–brain barrier transport of baclofen in rats by microdialysis. Pharm. Res. 12:1838–1844 (1995).
    Google ScholarLocate open access versionFindings
  • 66. Y. Deguchi, Y. Yokoyama, T. Sakamoto, H. Hayashi, T. Naito, S. Yamada, and R. Kimura. Brain distribution of 6-mercaptopurine is regulated by the efflux transport system in the blood– brain barrier. Life Sci. 66:649–662 (2000).
    Google ScholarLocate open access versionFindings
  • 67. M. R. Bouw, M. Gardmark, and M. Hammarlund-Udenaes. Pharmacokinetic-pharmacodynamic modelling of morphine transport across the blood–brain barrier as a cause of the antinociceptive effect delay in rats—a microdialysis study. Pharm. Res. 17:1220–1227 (2000).
    Google ScholarLocate open access versionFindings
  • 68. K. Tunblad, M. Hammarlund-Udenaes, and E. N. Jonsson. Influence of probenecid on the delivery of morphine-6glucuronide to the brain. Eur. J. Pharm. Sci. 24:49–57 (2005).
    Google ScholarLocate open access versionFindings
  • 69. E. Boström, U. S. Simonsson, and M. Hammarlund-Udenaes. 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 (2006).
    Google ScholarLocate open access versionFindings
  • 70. K. Tunblad, M. Hammarlund-Udenaes, and E. N. Jonsson. An integrated model for the analysis of pharmacokinetic data from microdialysis experiments. Pharm. Res. 21:1698–1707 (2004).
    Google ScholarLocate open access versionFindings
  • 71. A. Gupta, P. Chatelain, R. Massingham, E. N. Jonsson, and M. Hammarlund-Udenaes. 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 (2006).
    Google ScholarLocate open access versionFindings
  • 72. M. R. Bouw, R. Xie, K. Tunblad, and M. HammarlundUdenaes. Blood–brain barrier transport and brain distribution of morphine-6-glucuronide in relation to the antinociceptive effect in rats—pharmacokinetic/pharmacodynamic modelling. Br. J. Pharmacol. 134:1796–1804 (2001).
    Google ScholarLocate open access versionFindings
  • 73. E. Sam, S. Sarre, Y. Michotte, and N. Verbeke. Distribution of apomorphine enantiomers in plasma, brain tissue and striatal extracellular fluid. Eur. J. Pharmacol. 329:9–15 (1997).
    Google ScholarLocate open access versionFindings
  • 74. S. P. Khor, H. Bozigian, and M. Mayersohn. Potential error in the measurement of tissue to blood distribution coefficients in physiological pharmacokinetic modeling. Residual tissue blood. II. Distribution of phencyclidine in the rat. Drug Metab. Dispos. 19:486–490 (1991).
    Google ScholarLocate open access versionFindings
  • 75. T. S. Maurer, D. B. Debartolo, D. A. Tess, and D. O. Scott. Relationship between exposure and nonspecific binding of thirty-three central nervous system drugs in mice. Drug Metab. Dispos. 33:175–181 (2005).
    Google ScholarLocate open access versionFindings
  • 76. J. C. Kalvass and T. S. Maurer. Influence of nonspecific brain and plasma binding on CNS exposure: implications for rational drug discovery. Biopharm. Drug Dispos. 23:327–338 (2002).
    Google ScholarLocate open access versionFindings
  • 77. Y. Mano, S. Higuchi, and H. Kamimura. 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 (2002).
    Google ScholarLocate open access versionFindings
  • 78. R. E. Carson. PET physiological measurements using constant infusion. Nucl. Med. Biol. 27:657–660 (2000).
    Google ScholarLocate open access versionFindings
  • 79. C. Dagenais, C. L. Graff, and G. M. Pollack. Variable modulation of opioid brain uptake by P-glycoprotein in mice. Biochem. Pharmacol. 67:269–276 (2004).
    Google ScholarLocate open access versionFindings
  • 80. V. A. Levin. Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J. Med. Chem. 23:682–684 (1980).
    Google ScholarLocate open access versionFindings
  • 81. L. L. Radulovic, D. Turck, A. von Hodenberg, K. O. Vollmer, W. P. McNally, P. D. DeHart, B. J. Hanson, H. N. Bockbrader, and T. Chang. Disposition of gabapentin (neurontin) in mice, rats, dogs, and monkeys. Drug Metab. Dispos. 23:441–448 (1995).
    Google ScholarLocate open access versionFindings
  • 82. R. Xie and M. Hammarlund-Udenaes. Blood–brain barrier equilibration of codeine in rats studied with microdialysis. Pharm. Res. 15:570–575 (1998).
    Google ScholarLocate open access versionFindings
  • 83. K. Tunblad, E. N. Jonsson, and M. Hammarlund-Udenaes. Morphine blood–brain barrier transport is influenced by probenecid co-administration. Pharm. Res. 20:618–623 (2003).
    Google ScholarLocate open access versionFindings
  • 84. T. A. Aasmundstad, J. Morland, and R. E. Paulsen. Distribution of morphine 6-glucuronide and morphine across the blood– brain barrier in awake, freely moving rats investigated by in vivo microdialysis sampling. J. Pharmacol. Exp. Ther. 275:435– 441 (1995).
    Google ScholarLocate open access versionFindings
  • 85. P. Ederoth, K. Tunblad, R. Bouw, C. J. Lundberg, U. Ungerstedt, C. H. Nordstrom, and M. Hammarlund-Udenaes. Blood–brain barrier transport of morphine in patients with severe brain trauma. Br. J. Clin. Pharmacol. 57:427–435 (2004).
    Google ScholarLocate open access versionFindings
  • 86. K. Tunblad, P. Ederoth, A. Gardenfors, M. HammarlundUdenaes, and C. H. Nordstrom. Altered brain exposure of morphine in experimental meningitis studied with microdialysis. Acta Anaesthesiol. Scand. 48:294–301 (2004).
    Google ScholarLocate open access versionFindings
  • 87. S. L. Wong, Y. Wang, and R. J. Sawchuk. Analysis of zidovudine distribution to specific regions in rabbit brain using microdialysis. Pharm. Res. 9:332–338 (1992).
    Google ScholarLocate open access versionFindings
  • 88. E. C. de Lange, M. Danhof, A. G. de Boer, and D. D. Breimer. Critical factors of intracerebral microdialysis as a technique to determine the pharmacokinetics of drugs in rat brain. Brain Res. 666:1–8 (1994).
    Google ScholarLocate open access versionFindings
  • 89. N. H. Hendrikse, E. G. de Vries, L. Eriks-Fluks, W. T. van der Graaf, G. A. Hospers, A. T. Willemsen, W. Vaalburg, and E. J. Franssen. A new in vivo method to study P-glycoprotein transport in tumors and the blood–brain barrier. Cancer Res. 59:2411–2416 (1999).
    Google ScholarLocate open access versionFindings
  • 90. P. Hsiao, L. Sasongko, J. M. Link, D. A. Mankoff, M. Muzi, A. C. Collier, and J. D. Unadkat. Verapamil P-glycoprotein transport across the rat blood-brain barrier: cyclosporine, a concentration inhibition analysis, and comparison with human data. J. Pharmacol. Exp. Ther. 317:704–710 (2006).
    Google ScholarLocate open access versionFindings
  • 91. L. Sasongko, J. M. Link, M. Muzi, D. A. Mankoff, X. Yang, A. C. Collier, S. C. Shoner, and J. D. Unadkat. Imaging P-glycoprotein transport activity at the human blood–brain barrier with positron emission tomography. Clin. Pharmacol. Ther. 77:503–514 (2005).
    Google ScholarLocate open access versionFindings
  • 92. S. Syvännen, G. Blomquist, M. Sprycha, A. U. Hoglund, M. Roman, O. Eriksson, M. Hammarlund-Udenaes, B. Langstrom, and M. Bergstrom. Duration and degree of cyclosporin induced P-glycoprotein inhibition in the rat blood–brain barrier can be studied with PET. Neuroimage 32:1134–1141 (2006).
    Google ScholarLocate open access versionFindings
  • 93. S. Marchand, M. Chenel, I. Lamarche, C. Pariat, and W. Couet. Dose ranging pharmacokinetics and brain distribution of norfloxacin using microdialysis in rats. J. Pharm. Sci. 92:2458– 2465 (2003).
    Google ScholarLocate open access versionFindings
  • 94. S. Marchand, A. Forsell, M. Chenel, E. Comets, I. Lamarche, and W. Couet. Norfloxacin blood–brain barrier transport in rats is not affected by probenecid coadministration. Antimicrob. Agents Chemother. 50:371–373 (2006).
    Google ScholarLocate open access versionFindings
  • 95. M. E. Morgan, D. Singhal, and B. D. Anderson. Quantitative assessment of blood–brain barrier damage during microdialysis. J. Pharmacol. Exp. Ther. 277:1167–1176 (1996).
    Google ScholarLocate open access versionFindings
  • 96. I. Westergren, B. Nystrom, A. Hamberger, and B. B. Johansson. Intracerebral dialysis and the blood–brain barrier. J. Neurochem. 64:229–234 (1995).
    Google ScholarLocate open access versionFindings
  • 97. D. R. Groothuis, S. Ward, K. E. Schlageter, A. C. Itskovich, S. C. Schwerin, C. V. Allen, C. Dills, and R. M. Levy. Changes in blood–brain barrier permeability associated with insertion of brain cannulas and microdialysis probes. Brain Res. 803:218–230 (1998).
    Google ScholarLocate open access versionFindings
  • 98. B. Davies and T. Morris. Physiological parameters in laboratory animals and humans. Pharm. Res. 10:1093–1095 (1993).
    Google ScholarLocate open access versionFindings
  • 99. R. F. Reinoso, B. A. Telfer, and M. Rowland. Tissue water content in rats measured by desiccation. J. Pharmacol. Toxicol. Methods 38:87–92 (1997).
    Google ScholarLocate open access versionFindings
  • 100. U. Bickel, O. P. Schumacher, Y. S. Kang, and K. Voigt. Poor permeability of morphine 3-glucuronide and morphine 6glucuronide through the blood–brain barrier in the rat. J. Pharmacol. Exp. Ther. 278:107–113 (1996).
    Google ScholarLocate open access versionFindings
  • 101. W. B. Sisson and W. H. Oldendorf. Brain distribution spaces of mannitol-3H, inulin-14C, and dextran-14C in the rat. Am. J. Physiol. 221:214–217 (1971).
    Google ScholarLocate open access versionFindings
  • 102. Q. R. Smith, Y. Z. Ziylan, P. J. Robinson, and S. I. Rapoport. Kinetics and distribution volumes for tracers of different sizes in the brain plasma space. Brain Res. 462:1–9 (1988).
    Google ScholarLocate open access versionFindings
  • 103. R. P. Shockley and J. C. LaManna. Determination of rat cerebral cortical blood volume changes by capillary mean transit time analysis during hypoxia, hypercapnia and hyperventilation. Brain Res. 454:170–178 (1988).
    Google ScholarLocate open access versionFindings
  • 104. M. M. Todd, J. B. Weeks, and D. S. Warner. Microwave fixation for the determination of cerebral blood volume in rats. J. Cereb. Blood Flow Metab. 13:328–336 (1993).
    Google ScholarLocate open access versionFindings
  • 105. W. M. Pardridge and G. Fierer. Blood–brain barrier transport of butanol and water relative to N-isopropyl-p-iodoamphetamine as the internal reference. J. Cereb. Blood Flow Metab. 5:275–281 (1985).
    Google ScholarLocate open access versionFindings
  • 106. E. Johansson, S. Mansson, R. Wirestam, J. Svensson, J. S. Petersson, K. Golman, and F. Stahlberg. Cerebral perfusion assessment by bolus tracking using hyperpolarized 13C. Magn. Reson. Med. 51:464–472 (2004).
    Google ScholarLocate open access versionFindings
  • 107. E. M. Cornford, S. Hyman, M. E. Cornford, E. M. Landaw, and A. V. Delgado-Escueta. Interictal seizure resections show two configurations of endothelial Glut1 glucose transporter in the human blood–brain barrier. J. Cereb. Blood Flow Metab. 18:26– 42 (1998).
    Google ScholarLocate open access versionFindings
  • 108. M. W. Bradbury. The Concept of a Blood–Brain Barrier, Wiley, Chichester, 1979.
    Google ScholarFindings
  • 109. A. Gjedde and O. Christensen. Estimates of Michaelis–Menten constants for the two membranes of the brain endothelium. J. Cereb. Blood Flow Metab. 4:241–249 (1984).
    Google ScholarLocate open access versionFindings
  • 110. V. A. Levin, J. D. Fenstermacher, and C. S. Patlak. Sucrose and inulin space measurements of cerebral cortex in four mammalian species. Am. J. Physiol. 219:1528–1533 (1970).
    Google ScholarLocate open access versionFindings
  • 111. D. L. Woodward, D. J. Reed, and D. M. Woodbury. Extracellular space of rat cerebral cortex. Am. J. Physiol. 212:367–370 (1967).
    Google ScholarLocate open access versionFindings
  • 112. C. Nicholson and J. M. Phillips. Ion diffusion modified by tortuosity and volume fraction in the extracellular microenvironment of the rat cerebellum. J. Phys. 321:225–257 (1981).
    Google ScholarLocate open access versionFindings
  • 113. N. H. Bass and P. Lundborg. Postnatal development of bulk flow in the cerebrospinal fluid system of the albino rat: clearance of carboxyl-(14 C)inulin after intrathecal infusion. Brain Res. 52:323–332 (1973).
    Google ScholarLocate open access versionFindings
  • 114. H. Davson and M. B. Segal. Physiology of the CSF and Blood– Brain Barrier, CRC Press, Boca Raton, 1995.
    Google ScholarFindings
  • 115. H. Suzuki, Y. Sawada, Y. Sugiyama, T. Iga, and M. Hanano. Saturable transport of cimetidine from cerebrospinal fluid to blood in rats. J. Pharmacobio-Dyn. 8:73–76 (1985).
    Google ScholarLocate open access versionFindings
  • 116. P. P. Harnish and K. Samuel. Reduced cerebrospinal fluid production in the rat and rabbit by diatrizoate. Ventriculocisternal perfusion. Invest. Radiol. 23:534–536 (1988).
    Google ScholarLocate open access versionFindings
  • 117. H. Cserr. Potassium exchange between cerebrospinal fluid, plasma, and brain. Am. J. Physiol. 209:1219–1226 (1965).
    Google ScholarLocate open access versionFindings
  • 118. D. Wu, Y. S. Kang, U. Bickel, and W. M. Pardridge. Blood– brain barrier permeability to morphine-6-glucuronide is markedly reduced compared with morphine. Drug Metab. Dispos. 25:768–771 (1997).
    Google ScholarLocate open access versionFindings
  • 119. H. Duvernoy, S. Delon, and J. L. Vannson. The vascularization of the human cerebellar cortex. Brain Res. Bull. 11:419–480 (1983).
    Google ScholarLocate open access versionFindings
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