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Brain-to-Plasma Concentration Ratio and Unbound Partition Coefficient

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The ADME Encyclopedia

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Synonyms

Log BB, Kpuu, Brain to plasma concentration ratio, Unbund partition coefficient, Brain to plasma partition coefficient, Total brain-to-plasma ratio, Brain-to-plasma ratio

Definition

The brain-to-plasma concentration ratio (or total brain-to-plasma ratio, or simply, brain-to-plasma ratio, Kp, also referred to as B/P ratio or BB) is, as suggested by the name, the ratio between the total (bound and unbound) brain concentration Cbrain,ss and the total blood concentration Cblood.ss, at (pseudo)distribution equilibrium (steady state):

$$ {K}_p=\frac{C_{brain, ss}}{C_{blood, ss}} $$
(1)

Kp has been extensively used at preclinical drug development as an index of blood-brain barrier permeability and central nervous system (CNS) exposure. Alternatively to Eq. (1), it can also be computed as [1, 2]:

$$ {K}_p=\frac{AUC_{brain, ss}}{AUC_{blood, ss}} $$
(2)

where AUCbrain,ss denotes the area under the curve of total concentrations in the brain (at steady state) and AUCblood,ssrepresents...

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References

  1. Hammarlund-Udenaes M, Friden M, Syvanen S, Gupta A. On the rate and extent of drug delivery to the brain. Pharm Res. 2008;25:1737–50.

    Article  CAS  Google Scholar 

  2. Deo AK, Theil FP, Nicolas JM. Confounding parameters in preclinical assessment of blood−brain barrier permeation: an overview with emphasis on species differences and effect of disease states. Mol Pharm. 2013;10:1581–95.

    Article  CAS  Google Scholar 

  3. Di L, Rong H, Feng B. Demystifying brain penetration in central nervous system drug discovery. J Med Chem. 2013;56:2–12.

    Article  CAS  Google Scholar 

  4. Maurer TS, Debartolo DB, Tess DA, Scott DO. Relationship between exposure and nonspecific binding of thirty-three central nervous system drugs in mice. Drug Metab Dispos. 2005;33:175–81.

    Article  CAS  Google Scholar 

  5. Wager TT, Villalobos A, Verhoest PR, Hou X, Shaffer CL. Strategies to optimize the brain availability of central nervous system drug candidates. Expert Opin Drug Discovery. 2011;6:371–81.

    Article  CAS  Google Scholar 

  6. Talevi A, Bellera CL, Di Ianni M, Gantner M, Bruno-Blanch LE, Castro EA. CNS drug development – lost in translation? Mini Rev Med Chem. 2012;12:959–70.

    Article  CAS  Google Scholar 

  7. Kulkarni AD, Patel HM, Surana SJ, Belgamwar VS, Pardeshi CV. Brain–blood ratio: implications in brain drug delivery. Expert Opin Drug Deliv. 2016;13:85–92.

    Article  CAS  Google Scholar 

  8. Morales JF, Scioli Montoto S, Fagiolino P, Ruiz ME. Current state and future perspectives in QSAR models to predict blood-brain barrier penetration in central nervous system drug R&D. Mini Rev Med Chem. 2017;17:247–57.

    Article  CAS  Google Scholar 

  9. Wright DFB, Winter HR, Dufhull SB. Understanding the time course of pharmacological effect: a PKPD approach. Br J Clin Pharmacol. 2011;71:815–23.

    Article  CAS  Google Scholar 

  10. Smith DA, Di L, Kerns EH. The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery. Nat Rev Drug Discov. 2010;9:929–39.

    Article  CAS  Google Scholar 

  11. Hutchinson L, Kirk R. High drug attrition rates—where are we going wrong? Nat Rev Clin Oncol. 2011;8:189–90.

    Article  Google Scholar 

  12. Waring MJ, Arrowsmith J, Leach AR, Leeson PD, Mandrell S, Owen RM, et al. An analysis of the attrition of drug candidates from four major pharmaceutical companies. Nat Rev Drug Discov. 2015;14:475–86.

    Article  CAS  Google Scholar 

  13. Hurko O, Ryan JL. Translational research in central nervous system drug discovery. NeuroRx. 2005;2:671–82.

    Article  Google Scholar 

  14. Pangalos MN, Schechter LE, Hurko O. Drug development for CNS disorders: strategies for balancing risk and reducing attrition. Nat Rev Drug Discov. 2007;6:521–32.

    Article  CAS  Google Scholar 

  15. Safavi M, Sabourian R, Abdollahi M. The development of biomarkers to reduce attrition rate in drug discovery focused on oncology and central nervous system. Expert Opin Drug Discovery. 2016;11:939–56.

    Article  CAS  Google Scholar 

  16. Arrowsmith J, Miller P. Trial watch: phase II and phase III attrition rates 2011-2012. Nat Rev Drug Discov. 2013;12:569.

    Article  CAS  Google Scholar 

  17. Morgan P, Van Der Graaf PH, Arrowsmith J, Feltner DE, Drummond KS, Wegner CD, et al. Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving phase II survival. Drug Discov Today. 2012;17:419–24.

    Article  CAS  Google Scholar 

  18. Cook D, Brown D, Alexander R, March R, Morgan P, Satterthwaite G, et al. Lessons learned from the fate of AstraZeneca’s drug pipeline: a five-dimensional framework. Nat Rev Drug Discov. 2014;13:419–31.

    Article  CAS  Google Scholar 

  19. Culot M, Fabulas-da Costa A, Sevin E, Szorath E, Martinsson S, Renftel M, et al. A simple method for assessing free brain/free plasma ratios using an in vitro model of the blood brain barrier. PLoS One. 2014;8:e80634.

    Article  Google Scholar 

  20. Reichel A. The role of blood-brain barrier studies in the pharmaceutical industry. Curr Drug Metab. 2006;7:183–203.

    Article  CAS  Google Scholar 

  21. Doran A, Obach RS, Smith BJ, Hosea NA, Becker S, Callegari E, et al. 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. 2005;33:165–74.

    Article  CAS  Google Scholar 

  22. Boriss H. Brain availability is the key parameter for optimizing the permeability of central nervous system drugs. Drug Discovery. 2010;7:57–60.

    Article  Google Scholar 

  23. Ungerstedt U. Microdialysis--principles and applications for studies in animals and man. J Intern Med. 1991;230:365–73.

    Article  CAS  Google Scholar 

  24. Kalvass JC, Maurer TS. Influence of nonspecific brain and plasma binding on CNS exposure: implications for rational drug discovery. Biopharm Drug Dispos. 2002;23:327–38.

    Article  CAS  Google Scholar 

  25. Fridén M, Gupta A, Antonsson M, Bredberg U, Hammarlund-Udenaes M. In vitro methods for estimating unbound drug concentrations in the brain interstitial and intracellular fluids. Drug Metab Dispos. 2007;35:1711–9.

    Article  Google Scholar 

  26. Profaci CP, Munji RN, Pulido RS, Daneman R. The blood-brain barrier in health and disease: important unanswered questions. J Exp Med. 2020;217:e20190062.

    Article  Google Scholar 

  27. Couyoupetrou M, Gantner ME, Di Ianni ME, Palestro PH, Enrique AV, Gavernet L, et al. Computer-aided recognition of ABC transporters substrates and its application to the development of new drugs for refractory epilepsy. Mini Rev Med Chem. 2017;17:205–15.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Laboratory of Bioactive Research and Development (LIDeB), Department of Biological Sciences, Faculty of Exact Sciences, University of La Plata (UNLP), La Plata, Buenos Aires, Argentina

    Alan Talevi & Carolina L. Bellera

  2. Argentinean National Council of Scientific and Technical Research (CONICET) – CCT, La Plata, Buenos Aires, Argentina

    Alan Talevi & Carolina L. Bellera

Authors
  1. Alan Talevi
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  2. Carolina L. Bellera
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Correspondence to Alan Talevi .

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  1. Medicinal Chemistry, Department of Biological Sciences, Faculty of Exact Sciences, National University of la Plata (UNLP) - Argentinean National Council of Scientific and Technical Research (CONICET), La Plata, Buenos Aires, Argentina

    Alan Talevi

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Talevi, A., Bellera, C.L. (2021). Brain-to-Plasma Concentration Ratio and Unbound Partition Coefficient. In: The ADME Encyclopedia. Springer, Cham. https://doi.org/10.1007/978-3-030-51519-5_61-1

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  • DOI: https://doi.org/10.1007/978-3-030-51519-5_61-1

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  • Print ISBN: 978-3-030-51519-5

  • Online ISBN: 978-3-030-51519-5

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