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Pharmacokinetic Concepts in Brain Drug Delivery

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Drug Delivery to the Brain

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 33))

Abstract

This chapter presents the pharmacokinetic principles of blood-brain barrier (BBB) transport and the intra-brain distribution of small molecular drugs, in order to provide a basis for understanding drug delivery to the brain from a clinically relevant perspective. The most important concentrations to measure when determining drug distribution are those of the unbound drug, because it is the unbound drug that causes the pharmacological effect by interacting with the target. Therefore, this chapter also discusses the pharmacokinetic basis, the kind of information provided, and the in vivo relevance of the methods used to obtain reliable, therapeutically useful estimates of brain drug delivery. The main factors governing drug distribution to the brain are the permeability of the BBB to the drug (influx clearance), the extent of nonspecific binding to brain tissue, and the efflux clearance of the drug. The ratio of the influx and efflux clearances provides an estimation of the extent of drug equilibration across the BBB, described by the partition coefficient of unbound drug, Kp,uu,brain. This parameter is important, as active uptake and/or efflux transporters influence the brain concentrations of unbound drug in relation to those in plasma. The advantage of using Kp,uu,brain during the drug discovery process lies in its ability to predict the potential success of drugs intended for action within the brain or, conversely, of those with few or no side effects in the brain.

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Abbreviations

[plasma],u/[brain],u:

Ratio of plasma to brain unbound drug concentrations

Abrain:

Amount of drug per g brain tissue excluding blood

Aslice:

Amount of drug per g of brain slice

Atot.brain_inc_blood:

Amount of drug per g brain tissue including blood

AUCtot,brain:

Area under the total brain concentration-time curve

AUCtot,plasma:

Area under the total plasma concentration-time curve

AUCu,brainISF:

Area under the unbound brain ISF concentration-time curve

AUCu,plasma:

Area under the unbound plasma concentration-time curve

BBB:

Blood-brain barrier

BBMEC cells:

Bovine brain microvessel endothelial cells

BCSFB:

Blood-cerebrospinal fluid barrier

Caco-2:

Human epithelial colorectal adenocarcinoma cells

Cbuffer:

Concentration of drug in the buffer (brain slice method)

Ci:

Apparent concentration of drug in a peripheral brain compartment i

CLact_efflux:

Active efflux clearance from brain to blood at the BBB (μl/min/g_brain)

CLact_uptake:

Active uptake clearance from blood to brain at the BBB (μl/min/g_brain)

CLbulk_flow:

Clearance by bulk flow from brain ISF to CSF (μl/min/g_brain)

CLi:

Intercompartmental clearance between brain ISF and the peripheral brain compartment i

CLin:

Net influx clearance of drug to the brain (μl/min/g_brain), also called permeability clearance

CLmetabolism:

Metabolic clearance of drug in the brain or at the BBB (μl/min/g_brain)

CLout:

Net efflux clearance of drug from the brain (μl/min/g_brain)

CLpassive:

Passive diffusional clearance of drug at the BBB

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

Ctot,blood:

Total concentration of drug in blood

Ctot.plasma:

Total concentration of drug in plasma

Cu,brainISF:

Concentration of drug in the brain ISF (by definition unbound)

Cu,cell:

Average concentration of unbound drug in brain cells

Cu,plasma:

Unbound concentration in plasma

Cu,ss,brainISF:

Unbound steady-state concentration in brain ISF

Cu,ss,plasma:

Unbound steady-state concentration in plasma

ECF:

Extracellular fluid in the brain (also called ISF, interstitial fluid)

fu,brain:

Fraction of unbound drug in brain homogenate

fu,brain,corrected:

Fraction of unbound drug in brain homogenate after correction for pH partitioning based on the pKa(s) of the drug

fu,D:

Fraction of unbound drug in diluted brain homogenate

fu,plasma:

Fraction of unbound drug in plasma

GI:

Gastrointestinal

ICF:

Intracellular fluid in the brain

ISF:

Interstitial fluid in the brain (also called ECF, extracellular fluid)

Ki:

Inhibition constant

Kin:

In situ brain perfusion unidirectional transfer constant (a clearance estimate equal to PS or CLin) (μl/min/g_brain)

Kp,brain:

Partition coefficient (ratio) of total brain to total plasma drug concentrations

Kp,u,brain:

Ratio of total brain drug concentration to plasma unbound drug concentration

Kp,uu,brain:

Ratio of brain ISF to plasma unbound drug concentrations

Kp,uu,cell:

Ratio of brain ICF to ISF unbound drug concentrations

Kp,uu,CSF:

Ratio of CSF to plasma unbound drug concentrations

logBB:

Logarithm of the ratio of total brain to total plasma drug concentrations (equal to Kp)

MDCK cells:

Madin-Darby canine kidney cells

Mdr1:

Gene encoding for P-glycoprotein

Papp:

Unidirectional apparent permeability coefficient measured in the apical-to-basolateral direction (cm/s)

PBS:

Phosphate-buffered saline

PET:

Positron emission tomography

P-gp:

P-glycoprotein

PS:

Permeability surface area product (in this context equal to net influx clearance to the brain) (μl/min/g_brain)

Vblood:

Volume of blood in brain tissue

Vf:

Volume of buffer film remaining around the sampled brain slice

Vi:

Apparent volume of distribution of a peripheral brain compartment i

VISF:

Physiological (and apparent) volume of ISF

Vu,brain:

Volume of distribution of unbound drug in brain (ml/g_brain)

References

  • Abbott NJ (2004a) Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem Int 45:545–552

    Article  CAS  PubMed  Google Scholar 

  • Abbott NJ (2004b) Prediction of blood–brain barrier permeation in drug discovery from in vivo, in vitro and in silico models. Drug Discov Today Technol 1:407–416

    Article  CAS  PubMed  Google Scholar 

  • 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  PubMed  Google Scholar 

  • Abbott NJ, Pizzo ME, Preston JE, Janigro D, Thorne RG (2018) The role of brain barriers in fluid movement in the CNS: is there a 'glymphatic' system? Acta Neuropathol 135:387–407

    Article  CAS  PubMed  Google Scholar 

  • Abraham MH, Chadha HS, Mitchell RC (1995) Hydrogen-bonding. Part 36. Determination of blood brain distribution using octanol-water partition coefficients. Drug Des Discov 13:123–131

    CAS  PubMed  Google Scholar 

  • Agarwal S, Uchida Y, Mittapalli RK, Sane R, Terasaki T, Elmquist WF (2012) Quantitative proteomics of transporter expression in brain capillary endothelial cells isolated from P-gp, BCRP, and P-gp/BCRP knockout mice. Drug Metab Dispos

    Google Scholar 

  • Avdeef A (2011) How well can in vitro brain microcapillary endothelial cell models predict rodent in vivo blood-brain barrier permeability? Eur J Pharm Sci 43:109–124

    Article  CAS  PubMed  Google Scholar 

  • Avdeef A (2012) Absorption and drug development. Solubility, permeability and charge state. Wiley

    Book  Google Scholar 

  • Avdeef A, Sun N (2011) A new in situ brain perfusion flow correction method for lipophilic drugs based on the pH-dependent crone-Renkin equation. Pharm Res 28:517–530

    Article  CAS  PubMed  Google Scholar 

  • Banks WA, Jaspan JB, Kastin AJ (1997) Effect of diabetes mellitus on the permeability of the blood-brain barrier to insulin. Peptides 18:1577–1584

    Article  CAS  PubMed  Google Scholar 

  • Bauer M, Zeitlinger M, Karch R, Matzneller P, Stanek J, Jager W, Bohmdorfer M, Wadsak W, Mitterhauser M, Bankstahl JP, Loscher W, Koepp M, Kuntner C, Muller M, Langer O (2012) Pgp-mediated interaction between (R)-[11C]verapamil and tariquidar at the human blood-brain barrier: a comparison with rat data. Clin Pharmacol Ther 91:227–233

    Article  CAS  PubMed  Google Scholar 

  • Bauer M, Karch R, Zeitlinger M, Philippe C, Romermann K, Stanek J, Maier-Salamon A, Wadsak W, Jager W, Hacker M, Muller M, Langer O (2015) Approaching complete inhibition of P-glycoprotein at the human blood-brain barrier: an (R)-[11C]verapamil PET study. J Cereb Blood Flow Metab 35:743–746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bengtsson J, Ederoth P, Ley D, Hansson S, Amer-Wahlin I, Hellstrom-Westas L, Marsal K, Nordstrom CH, Hammarlund-Udenaes M (2009) The influence of age on the distribution of morphine and morphine-3-glucuronide across the blood-brain barrier in sheep. Br J Pharmacol 157:1085–1096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  • Bostrom E, Simonsson US, Hammarlund-Udenaes M (2005) Oxycodone pharmacokinetics and pharmacodynamics in the rat in the presence of the P-glycoprotein inhibitor PSC833. J Pharm Sci 94:1060–1066

    Article  PubMed  CAS  Google Scholar 

  • 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  PubMed  CAS  Google Scholar 

  • 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  PubMed  CAS  Google Scholar 

  • Bouw MR, Gardmark M, Hammarlund-Udenaes M (2000) 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

    Article  CAS  PubMed  Google Scholar 

  • Bouw MR, Xie R, Tunblad K, Hammarlund-Udenaes M (2001) 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Broccatelli F, Larregieu CA, Cruciani G, Oprea TI, Benet LZ (2012) Improving the prediction of the brain disposition for orally administered drugs using BDDCS. Adv Drug Deliv Rev 64:95–109

    Article  CAS  PubMed  Google Scholar 

  • Chen H, Winiwarter S, Friden M, Antonsson M, Engkvist O (2011) In silico prediction of unbound brain-to-plasma concentration ratio using machine learning algorithms. J Mol Graph Model 29:985–995

    Article  CAS  PubMed  Google Scholar 

  • Chen X, Slattengren T, de Lange ECM, Smith DE, Hammarlund-Udenaes M (2017) Revisiting atenolol as a low passive permeability marker. Fluids Barriers CNS 14:30

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cordon-cardo C, O’Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, Bertino JR (1989) Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci U S A 86:695–698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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  PubMed  Google Scholar 

  • 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  PubMed  Google Scholar 

  • 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  PubMed  Google Scholar 

  • Dai H, Chen Y, Elmquist WF, Yang H, Wang Q, Elmquist WF (2005) Distribution of the novel antifolate pemetrexed to the brain. J Pharmacol Exp Ther 315:222–229

    Article  CAS  PubMed  Google Scholar 

  • 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  PubMed  Google Scholar 

  • Deguchi Y, Yokoyama Y, Sakamoto T, Hayashi H, Naito T, Yamada S, Kimura R (2000) Brain distribution of 6-mercaptopurine is regulated by the efflux transport system in the blood-brain barrier. Life Sci 66:649–662

    Article  CAS  PubMed  Google Scholar 

  • Di L, Kerns EH, Bezar IF, Petusky SL, Huang Y (2009) Comparison of blood-brain barrier permeability assays: in situ brain perfusion, MDR1-MDCKII and PAMPA-BBB. J Pharm Sci 98:1980–1991

    Article  CAS  PubMed  Google Scholar 

  • 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  PubMed  Google Scholar 

  • Di L, Artursson P, Avdeef A, Ecker GF, Faller B, Fischer H, Houston JB, Kansy M, Kerns EH, Kramer SD, Lennernas H, Sugano K (2012) Evidence-based approach to assess passive diffusion and carrier-mediated drug transport. Drug Discov Today 17:905–912

    Article  CAS  PubMed  Google Scholar 

  • Doran A, Obach RS, Smith BJ, Hosea NA, Becker S, Callegari E, Chen C, Chen X, Choo E, Cianfrogna J, Cox LM, Gibbs JP, Gibbs MA, Hatch H, Hop CE, Kasman IN, Laperle J, Liu J, Liu X, Logman M, Maclin D, Nedza FM, Nelson F, Olson E, Rahematpura S, Raunig D, Rogers S, Schmidt K, Spracklin DK, Szewc M, Troutman M, Tseng E, Tu M, van Deusen JW, Venkatakrishnan K, Walens G, Wang EQ, Wong D, Yasgar AS, Zhang C (2005) The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the MDR1A/1B knockout mouse model. Drug Metab Dispos 33:165–174

    Article  CAS  PubMed  Google Scholar 

  • Doran AC, Osgood SM, Mancuso JY, Shaffer CL (2012) An evaluation of using rat-derived single-dose neuropharmacokinetic parameters to project accurately large animal unbound brain drug concentrations. Drug Metab Dispos 40:2162–2173

    Article  CAS  PubMed  Google Scholar 

  • Dubey RK, Mcallister CB, Inoue M, Wilkinson GR (1989) Plasma binding and transport of diazepam across the blood-brain barrier. No evidence for in vivo enhanced dissociation. J Clin Invest 84:1155–1159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ederoth P, Tunblad K, Bouw R, Lundberg CJ, Ungerstedt U, Nordstrom CH, Hammarlund-Udenaes M (2004) Blood-brain barrier transport of morphine in patients with severe brain trauma. Br J Clin Pharmacol 57:427–435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fan Y, Unwalla R, Denny RA, Di L, Kerns EH, Diller DJ, Humblet C (2010) Insights for predicting blood-brain barrier penetration of CNS targeted molecules using QSPR approaches. J Chem Inf Model 50:1123–1133

    Article  CAS  PubMed  Google Scholar 

  • Fenstermacher J, Gross P, Sposito N, Acuff V, Pettersen S, Gruber K (1988) Structural and functional variations in capillary systems within the brain. Ann N Y Acad Sci 529:21–30

    Article  CAS  PubMed  Google Scholar 

  • 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  PubMed  Google Scholar 

  • Friden M, Ducrozet F, Middleton B, Antonsson M, Bredberg U, Hammarlund-Udenaes M (2009a) 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  PubMed  Google Scholar 

  • Friden M, Winiwarter S, Jerndal G, Bengtsson O, Wan H, Bredberg U, Hammarlund-Udenaes M, Antonsson M (2009b) 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  PubMed  Google Scholar 

  • 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  PubMed  Google Scholar 

  • 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  PubMed  Google Scholar 

  • Garberg P, Ball M, Borg N, Cecchelli R, Fenart L, Hurst RD, Lindmark T, Mabondzo A, Nilsson JE, Raub TJ, Stanimirovic D, Terasaki T, Oberg JO, Osterberg T (2005) In vitro models for the blood-brain barrier. Toxicol In Vitro 19:299–334

    Article  CAS  PubMed  Google Scholar 

  • 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  PubMed  Google Scholar 

  • Golden PL, Pollack GM (1998) Rationale for influx enhancement versus efflux blockade to increase drug exposure to the brain. Biopharm Drug Dispos 19:263–272

    Article  CAS  PubMed  Google Scholar 

  • Gunn RN, Summerfield SG, Salinas CA, Read KD, Guo Q, Searle GE, Parker CA, Jeffrey P, Laruelle M (2012) Combining PET biodistribution and equilibrium dialysis assays to assess the free brain concentration and BBB transport of CNS drugs. J Cereb Blood Flow Metab 32:874–883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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  PubMed  Google Scholar 

  • Gustafsson S, Sehlin D, Lampa E, Hammarlund-Udenaes M, Loryan I (2019) Heterogeneous drug tissue binding in brain regions of rats, Alzheimer's patients and controls: impact on translational drug development. Sci Rep 9:5308

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hakkarainen JJ, Jalkanen AJ, Kaariainen TM, Keski-Rahkonen P, Venalainen T, Hokkanen J, Monkkonen J, Suhonen M, Forsberg MM (2010) Comparison of in vitro cell models in predicting in vivo brain entry of drugs. Int J Pharm 402:27–36

    Article  CAS  PubMed  Google Scholar 

  • 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  PubMed  Google Scholar 

  • Hammarlund-Udenaes M (2010) Active-site concentrations of chemicals - are they a better predictor of effect than plasma/organ/tissue concentrations? Basic Clin Pharmacol Toxicol 106:215–220

    Article  CAS  PubMed  Google Scholar 

  • Hammarlund-Udenaes M (2013) Microdialysis in CNS PKPD research: unraveling unbound concentrations. In: Müller M (ed) Microdialysis in drug development. Springer, New York

    Google Scholar 

  • Hammarlund-Udenaes M, Paalzow LK, de Lange EC (1997) Drug equilibration across the blood-brain barrier--pharmacokinetic considerations based on the microdialysis method. Pharm Res 14:128–134

    Article  CAS  PubMed  Google Scholar 

  • 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  PubMed  Google Scholar 

  • 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  PubMed  Google Scholar 

  • Hsiao P, Unadkat JD (2012) P-glycoprotein-based loperamide-cyclosporine drug interaction at the rat blood-brain barrier: prediction from in vitro studies and extrapolation to humans. Mol Pharm 9:629–633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu Y, Rip J, Gaillard PJ, de Lange ECM, Hammarlund-Udenaes M (2017) The impact of liposomal formulations on the release and brain delivery of methotrexate: an in vivo microdialysis study. J Pharm Sci 106:2606–2613

    Article  CAS  PubMed  Google Scholar 

  • Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med 4:147ra111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ito K, Uchida Y, Ohtsuki S, Aizawa S, Kawakami H, Katsukura Y, Kamiie J, Terasaki T (2011) Quantitative membrane protein expression at the blood-brain barrier of adult and younger cynomolgus monkeys. J Pharm Sci 100:3939–3950

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Kaitin KI (2008) Obstacles and opportunities in new drug development. Clin Pharmacol Ther 83:210–212

    Article  CAS  PubMed  Google Scholar 

  • 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 Therapeutics 277:1550–1559

    CAS  Google Scholar 

  • 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  PubMed  Google Scholar 

  • Kalvass JC, Maurer TS, Pollack GM (2007a) 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 35:660–666

    Article  CAS  PubMed  Google Scholar 

  • Kalvass JC, Olson ER, Cassidy MP, Selley DE, Pollack GM (2007b) Pharmacokinetics and pharmacodynamics of seven opioids in P-glycoprotein-competent mice: assessment of unbound brain EC50,u and correlation of in vitro, preclinical, and clinical data. J Pharmacol Exp Ther 323:346–355

    Article  CAS  PubMed  Google Scholar 

  • Kalvass JC, Polli JW, Bourdet DL, Feng B, Huang SM, Liu X, Smith QR, Zhang LK, Zamek-Gliszczynski MJ, International Transporter, C (2013) Why clinical modulation of efflux transport at the human blood-brain barrier is unlikely: the ITC evidence-based position. Clin Pharmacol Ther 94:80–94

    Article  CAS  PubMed  Google Scholar 

  • Kola I, Landis J (2004) Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 3:711–715

    Article  CAS  PubMed  Google Scholar 

  • Kurosawa T, Higuchi K, Okura T, Kobayashi K, Kusuhara H, Deguchi Y (2017) Involvement of proton-coupled organic cation antiporter in Varenicline transport at blood-brain barrier of rats and in human brain capillary endothelial cells. J Pharm Sci 106:2576–2582

    Article  CAS  PubMed  Google Scholar 

  • Kusuhara H, Sugiyama Y (2009) In vitro-in vivo extrapolation of transporter-mediated clearance in the liver and kidney. Drug Metab Pharmacokinet 24:37–52

    Article  CAS  PubMed  Google Scholar 

  • Lanevskij K, Japertas P, Didziapetris R (2013) Improving the prediction of drug disposition in the brain. Expert Opin Drug Metab Toxicol

    Google Scholar 

  • Large CH, Kalinichev M, Lucas A, Carignani C, Bradford A, Garbati N, Sartori I, Austin NE, Ruffo A, Jones DN, Alvaro G, Read KD (2009) The relationship between sodium channel inhibition and anticonvulsant activity in a model of generalised seizure in the rat. Epilepsy Res 85:96–106

    Article  CAS  PubMed  Google Scholar 

  • Levin VA (1980) Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J Med Chem 23:682–684

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Liu X, Chen C (2005) Strategies to optimize brain penetration in drug discovery. Curr Opin Drug Discov Devel 8:505–512

    CAS  PubMed  Google Scholar 

  • Liu X, Tu M, Kelly RS, Chen C, Smith BJ (2004) Development of a computational approach to predict blood-brain barrier permeability. Drug Metab Dispos 32:132–139

    Article  CAS  PubMed  Google Scholar 

  • Liu X, Smith BJ, Chen C, Callegari E, Becker SL, Chen X, Cianfrogna J, Doran AC, Doran SD, Gibbs JP, Hosea N, Liu J, Nelson FR, Szewc MA, van Deusen J (2005) 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

    Article  CAS  PubMed  Google Scholar 

  • Liu X, Chen C, Smith BJ (2008) Progress in brain penetration evaluation in drug discovery and development. J Pharmacol Exp Ther 325:349–356

    Article  CAS  PubMed  Google Scholar 

  • Liu X, van Natta K, Yeo H, Vilenski O, Weller PE, Worboys PD, Monshouwer M (2009) 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 37:787–793

    Article  CAS  PubMed  Google Scholar 

  • 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  PubMed  PubMed Central  Google Scholar 

  • Loryan I, Sinha V, Mackie C, van Peer A, Drinkenburg W, Vermeulen A, Morrison D, Monshouwer M, Heald D, Hammarlund-Udenaes M (2014) Mechanistic understanding of brain drug disposition to optimize the selection of potential neurotherapeutics in drug discovery. Pharm Res 31:2203–2219

    Article  CAS  PubMed  Google Scholar 

  • Loryan I, Melander E, Svensson M, Payan M, Konig F, Jansson B, Hammarlund-Udenaes M (2016) In-depth neuropharmacokinetic analysis of antipsychotics based on a novel approach to estimate unbound target-site concentration in CNS regions: link to spatial receptor occupancy. Mol Psychiatry

    Google Scholar 

  • Loryan I, Hoppe E, Hansen K, Held F, Kless A, Linz K, Marossek V, Nolte B, Ratcliffe P, Saunders D, Terlinden R, Wegert A, Welbers A, Will O, Hammarlund-Udenaes M (2017) Quantitative assessment of drug delivery to tissues and association with Phospholipidosis: A case study with two structurally related diamines in development. Mol Pharm 14:4362–4373

    Article  CAS  PubMed  Google Scholar 

  • 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  PubMed  Google Scholar 

  • Matsuda A, Karch R, Bauer M, Traxl A, Zeitlinger M, Langer O (2017) A prediction method for P-glycoprotein-mediated drug-drug interactions at the human blood-brain barrier from blood concentration-time profiles, validated with PET data. J Pharm Sci 106:2780–2786

    Article  CAS  PubMed  Google Scholar 

  • Maurer TS, Debartolo DB, Tess DA, Scott DO (2005) Relationship between exposure and nonspecific binding of thirty-three central nervous system drugs in mice. Drug Metab Dispos 33:175–181

    Article  CAS  PubMed  Google Scholar 

  • Mensch J, Jaroskova L, Sanderson W, Melis A, Mackie C, Verreck G, Brewster ME, Augustijns P (2010a) Application of PAMPA-models to predict BBB permeability including efflux ratio, plasma protein binding and physicochemical parameters. Int J Pharm 395:182–197

    Article  CAS  PubMed  Google Scholar 

  • Mensch J, Melis A, Mackie C, Verreck G, Brewster ME, Augustijns P (2010b) Evaluation of various PAMPA models to identify the most discriminating method for the prediction of BBB permeability. Eur J Pharm Biopharm 74:495–502

    Article  CAS  PubMed  Google Scholar 

  • Muehlbacher M, Spitzer GM, Liedl KR, Kornhuber J (2011) Qualitative prediction of blood-brain barrier permeability on a large and refined dataset. J Comput Aided Mol Des 25:1095–1106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nicholson C, Phillips JM (1981) Ion diffusion modified by tortuosity and volume fraction in the extracellular microenvironment of the rat cerebellum. J Physiol 321:225–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Norinder U, Haeberlein M (2002) Computational approaches to the prediction of the blood-brain distribution. Adv Drug Deliv Rev 54:291–313

    Article  CAS  PubMed  Google Scholar 

  • Norinder U, Sjoberg P, Osterberg T (1998) Theoretical calculation and prediction of brain-blood partitioning of organic solutes using MolSurf parametrization and PLS statistics. J Pharm Sci 87:952–959

    Article  CAS  PubMed  Google Scholar 

  • Ooie T, Terasaki T, Suzuki H, Sugiyama Y (1997) Kinetic evidence for active efflux transport across the blood-brain barrier of quinolone antibiotics. J Pharmacol Exp Therapeutics 283:293–304

    CAS  Google Scholar 

  • Padowski JM, Pollack GM (2011) Influence of time to achieve substrate distribution equilibrium between brain tissue and blood on quantitation of the blood-brain barrier P-glycoprotein effect. Brain Res 1426:1–17

    Article  CAS  PubMed  Google Scholar 

  • Pardridge WM (2004) Log(BB), PS products and in silico models of drug brain penetration.[comment]. Drug Discov Today 9:392–393

    Article  PubMed  Google Scholar 

  • Pardridge WM, Boado RJ, Black KL, Cancilla PA (1992) Blood-brain barrier and new approaches to brain drug delivery. West J Med 156:281–286

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rao VV, Dahlheimer JL, Bardgett ME, Snyder AZ, Finch RA, Sartorelli AC, Piwnica-Worms D (1999) Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier. Proc Natl Acad Sci U S A 96:3900–3905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reinoso RF, Telfer BA, Rowland M (1997) Tissue water content in rats measured by desiccation. J Pharmacol Toxicol Methods 38:87–92

    Article  CAS  PubMed  Google Scholar 

  • Rosenberg GA, Kyner WT, Estrada E (1980) Bulk flow of brain interstitial fluid under normal and hyperosmolar conditions. Am J Physiol 238:F42–F49

    CAS  PubMed  Google Scholar 

  • Rowland M, Tozer T (2011) Clinical pharmacokinetics and pharmacodynamics. Concepts and applications., Baltimore and Philadephia, Lippincott, Williams & Wilkins

    Google Scholar 

  • Sadeque AJ, Wandel C, He H, Shah S, wood, A. J. (2000) Increased drug delivery to the brain by P-glycoprotein inhibition. Clin Pharmacol Ther 68:231–237

    Article  CAS  PubMed  Google Scholar 

  • 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  PubMed  Google Scholar 

  • Sasongko L, Link JM, Muzi M, Mankoff DA, Yang X, Collier AC, Shoner SC, Unadkat JD (2005) Imaging P-glycoprotein transport activity at the human blood-brain barrier with positron emission tomography. Clin Pharmacol Ther 77:503–514

    Article  CAS  PubMed  Google Scholar 

  • Schinkel AH, Wagenaar E, Mol CA, Van Deemter L (1996) P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest 97:2517–2524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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  PubMed  Google Scholar 

  • Shityakov S, Neuhaus W, Dandekar T, Forster C (2013) Analysing molecular polar surface descriptors to predict blood-brain barrier permeation. Int J Comput Biol Drug Des 6:146–156

    Article  CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  • Stevens J, Ploeger BA, Hammarlund-Udenaes M, Osswald G, van der Graaf PH, Danhof M, de Lange EC (2012) Mechanism-based PK-PD model for the prolactin biological system response following an acute dopamine inhibition challenge: quantitative extrapolation to humans. J Pharmacokinet Pharmacodyn

    Google Scholar 

  • Summerfield SG, Stevens AJ, Cutler L, del Carmen Osuna M, Hammond B, Tang SP, Hersey A, Spalding DJ, Jeffrey P (2006) Improving the in vitro prediction of in vivo central nervous system penetration: integrating permeability, P-glycoprotein efflux, and free fractions in blood and brain. J Pharmacol Exp Ther 316:1282–1290

    Article  CAS  PubMed  Google Scholar 

  • Summerfield SG, Read K, Begley DJ, Obradovic T, Hidalgo IJ, Coggon S, Lewis AV, Porter RA, Jeffrey P (2007) Central nervous system drug disposition: the relationship between in situ brain permeability and brain free fraction. J Pharmacol Exp Ther 322:205–213

    Article  CAS  PubMed  Google Scholar 

  • Summerfield SG, Lucas AJ, Porter RA, Jeffrey P, Gunn RN, Read KR, Stevens AJ, Metcalf AC, Osuna MC, Kilford PJ, Passchier J, Ruffo AD (2008) Toward an improved prediction of human in vivo brain penetration. Xenobiotica 38:1518–1535

    Article  CAS  PubMed  Google Scholar 

  • Summerfield SG, Zhang Y, Liu H (2016) Examining the uptake of central nervous system drugs and candidates across the blood-brain barrier. J Pharmacol Exp Ther 358:294–305

    Article  CAS  PubMed  Google Scholar 

  • Sun H (2004) A universal molecular descriptor system for prediction of logP, logS, logBB, and absorption. J Chem Inf Comput Sci 44:748–757

    Article  CAS  PubMed  Google Scholar 

  • Sun H, Dai H, Shaik N, Elmquist WF, BUNGAY, P. M. (2003) Drug efflux transporters in the CNS. Adv Drug Deliv Rev 55:83–105

    Article  CAS  PubMed  Google Scholar 

  • 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

    Google Scholar 

  • Syvanen S, Xie R, Sahin S, Hammarlund-Udenaes M (2006) Pharmacokinetic consequences of active drug efflux at the blood-brain barrier. Pharm Res 23:705–717

    Article  CAS  PubMed  Google Scholar 

  • 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  PubMed  Google Scholar 

  • Tamai I, Tsuji A (2000) Transporter-mediated permeation of drugs across the blood-brain barrier. J Pharm Sci 89:1371–1388

    Article  CAS  PubMed  Google Scholar 

  • Tega Y, Akanuma S, Kubo Y, Terasaki T, Hosoya K (2013) Blood-to-brain influx transport of nicotine at the rat blood-brain barrier: involvement of a pyrilamine-sensitive organic cation transport process. Neurochem Int 62:173–181

    Article  CAS  PubMed  Google Scholar 

  • Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC (1989) Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P170: evidence for localization in brain capillaries and crossreactivity of one antibody with a muscle protein. J Histochem Cytochem 37:159–164

    Article  CAS  PubMed  Google Scholar 

  • Tsuji A, Terasaki T, Takabatake Y, Tenda Y, Tamai I, Yamashima T, Moritani S, Tsuruo T, Yamashita J (1992) P-glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells. Life Sci 51:1427–1437

    Article  CAS  PubMed  Google Scholar 

  • 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  PubMed  Google Scholar 

  • Tunblad K, Ederoth P, Gardenfors A, Hammarlund-Udenaes M, Nordstrom CH (2004a) Altered brain exposure of morphine in experimental meningitis studied with microdialysis. Acta Anaesthesiol Scand 48:294–301

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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  PubMed  Google Scholar 

  • Uchida Y, Ohtsuki S, Kamiie J, Terasaki T (2011a) 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 339:579–588

    Article  CAS  PubMed  Google Scholar 

  • Uchida Y, Ohtsuki S, Katsukura Y, Ikeda C, Suzuki T, Kamiie J, Terasaki T (2011b) Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. J Neurochem 117:333–345

    Article  CAS  PubMed  Google Scholar 

  • Uchida Y, Yagi Y, Takao M, Tano M, Umetsu M, Hirano S, Usui T, Tachikawa M, Terasaki T (2020) Comparison of absolute protein abundances of transporters and receptors among blood-brain barriers at different cerebral regions and the blood-spinal cord barrier in humans and rats. Mol Pharm 17:2006–2020

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Welty DF (1996) The simultaneous estimation of the influx and efflux blood-brain barrier permeabilities of gabapentin using a microdialysis-pharmacokinetic approach. Pharm Res 13:398–403

    Article  CAS  PubMed  Google Scholar 

  • 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  PubMed  Google Scholar 

  • 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  PubMed  PubMed Central  Google Scholar 

  • Westerhout J, Smeets J, Danhof M, Lange DE, E. C. (2013) The impact of P-gp functionality on non-steady state relationships between CSF and brain extracellular fluid. J Pharmacokinet Pharmacodyn 40:327–342

    Article  PubMed  PubMed Central  Google Scholar 

  • Westerhout J, van Den Berg DJ, Hartman R, Danhof M, de Lange EC (2014) Prediction of methotrexate CNS distribution in different species - influence of disease conditions. Eur J Pharm Sci 57:11–24

    Article  CAS  PubMed  Google Scholar 

  • Xie R, Hammarlund-Udenaes M (1998) Blood-brain barrier equilibration of codeine in rats studied with microdialysis. Pharm Res 15:570–575

    Article  CAS  PubMed  Google Scholar 

  • Xie R, Bouw MR, Hammarlund-Udenaes M (2000) Modelling of the blood-brain barrier transport of morphine-3-glucuronide studied using microdialysis in the rat: involvement of probenecid-sensitive transport. Br J Pharmacol 131:1784–1792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamamoto Y, Valitalo PA, van den Berg DJ, Hartman R, van den Brink W, Wong YC, Huntjens DR, Proost JH, Vermeulen A, Krauwinkel W, Bakshi S, Aranzana-Climent V, Marchand S, Dahyot-Fizelier C, Couet W, Danhof M, van Hasselt JG, de Lange EC (2017) A generic multi-compartmental CNS distribution model structure for 9 drugs allows prediction of human brain target site concentrations. Pharm Res 34:333–351

    Article  CAS  PubMed  Google Scholar 

  • Young RC, Mitchell RC, Brown TH, Ganellin CR, Griffiths R, Jones M, Rana KK, Saunders D, Smith IR, Sore NE et al (1988) Development of a new physicochemical model for brain penetration and its application to the design of centrally acting H2 receptor histamine antagonists. J Med Chem 31:656–671

    Article  CAS  PubMed  Google Scholar 

  • Yusof SR, Mohd Uzid M, Teh EH, Hanapi NA, Mohideen M, Mohamad Arshad AS, Mordi MN, Loryan I, Hammarlund-Udenaes M (2019) Rate and extent of mitragynine and 7-hydroxymitragynine blood-brain barrier transport and their intra-brain distribution: the missing link in pharmacodynamic studies. Addict Biol 24:935–945

    Article  CAS  PubMed  Google Scholar 

  • Zhao R, Kalvass JC, Pollack GM (2009) Assessment of blood-brain barrier permeability using the in situ mouse brain perfusion technique. Pharm Res 26:1657–1664

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Translational PKPD Group, Department of Pharmacy, Uppsala University, Uppsala, Sweden

    Margareta Hammarlund-Udenaes

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Correspondence to Margareta Hammarlund-Udenaes .

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  1. Research Division of Systems Pharmacology and Pharmacy, Leiden University, Leiden, The Netherlands

    Elizabeth C.M. de Lange

  2. Department of Pharmacy, Uppsala University, Uppsala, Sweden

    Margareta Hammarlund-Udenaes

  3. Biology Discovery, Denali Therapeutics, South San Francisco, CA, USA

    Robert G. Thorne

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Hammarlund-Udenaes, M. (2022). Pharmacokinetic Concepts in Brain Drug Delivery. In: de Lange, E.C., Hammarlund-Udenaes, M., Thorne, R.G. (eds) Drug Delivery to the Brain. AAPS Advances in the Pharmaceutical Sciences Series, vol 33. Springer, Cham. https://doi.org/10.1007/978-3-030-88773-5_7

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