Skip to main content

Advertisement

SpringerLink
Log in

The influence of distributional kinetics into a peripheral compartment on the pharmacokinetics of substrate partitioning between blood and brain tissue

  • Published:
Journal of Pharmacokinetics and Pharmacodynamics Aims and scope Submit manuscript

Abstract

Development of CNS-targeted agents often focuses on identifying compounds with “good” CNS exposure (brain-to-blood partitioning >1). Some compounds undergoing enterohepatic recycling (ER) evidence a partition coefficient, K p,brain (expressed as C brain /C plasma), that exceeds and then decreases to (i.e., overshoots) a plateau (distribution equilibrium) value, rather than increasing monotonically to this value. This study tested the hypothesis that overshoot in K p,brain is due to substrate residence in a peripheral compartment. Simulations were based on a 3-compartment model with distributional clearances between central and brain (CL br) and central and peripheral (CL d) compartments and irreversible clearance from the central compartment (CL). Parameters were varied to investigate the relationship between overshoot and peripheral compartment volume (V p), and how this relationship was modulated by other model parameters. Overshoot magnitude and duration were characterized as peak C brain/C plasma relative to the plateau value (%OS) and time to reach plateau (TRP). Except for systems with high CL d, increasing V p increased TRP and %OS. Increasing brain (V br) or central (V c) distribution volumes eliminated V p-related OS. Parallel increases in all clearances shortened TRP, but did not alter %OS. Increasing either CL or CL d individually increased %OS related to V p, while increasing CL br decreased %OS. Under realistic peripheral distribution scenarios, C brain/C plasma may overshoot substantially K p,brain at distribution equilibrium. This observation suggests potential for erroneous assessment of brain disposition, particularly for compounds which exhibit a large apparent V p, and emphasizes the need for complete understanding of distributional kinetics when evaluating brain uptake.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13

Similar content being viewed by others

References

  1. Weaver DF, Weaver CA (2011) Exploring neurotherapeutic space: how many neurological drugs exist (or could exist)? J Pharm Pharmacol 63(1):136–139

    Article  PubMed  CAS  Google Scholar 

  2. Bernacki J, Dobrowolska A, Nierwinska K, Malecki A (2008) Physiology and pharmacological role of the blood-brain barrier. Pharmacol Rep 60(5):600–622

    PubMed  CAS  Google Scholar 

  3. Neuwelt EA, Bauer B, Fahlke C, Fricker G, Iadecola C, Janigro D, Leybaert L, Molnar Z, O’Donnell ME, Povlishock JT, Saunders NR, Sharp F, Stanimirovic D, Watts RJ, Drewes LR (2011) Engaging neuroscience to advance translational research in brain barrier biology. Nat Rev Neurosci 12(3):169–182

    Article  PubMed  CAS  Google Scholar 

  4. Pardridge WM (2007) Drug targeting to the brain. Pharm Res 24(9):1733–1744

    Article  PubMed  CAS  Google Scholar 

  5. Jeffrey P, Summerfield SG (2007) Challenges for blood-brain barrier (BBB) screening. Xenobiotica 37(10–11):1135–1151

    Article  PubMed  CAS  Google Scholar 

  6. Patel MM, Goyal BR, Bhadada SV, Bhatt JS, Amin AF (2009) Getting into the brain: approaches to enhance brain drug delivery. CNS Drugs 23(1):35–58

    Article  PubMed  CAS  Google Scholar 

  7. Kalvass JC, Maurer TS, Pollack GM (2007) 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(4):660–666

    Article  PubMed  CAS  Google Scholar 

  8. Hammarlund-Udenaes M, Bredberg U, Friden M (2009) Methodologies to assess brain drug delivery in lead optimization. Curr Top Med Chem 9(2):148–162

    Article  PubMed  CAS  Google Scholar 

  9. Liu X, Chen C, Smith BJ (2008) Progress in brain penetration evaluation in drug discovery and development. J Pharmacol Exp Ther 325(2):349–356

    Article  PubMed  CAS  Google Scholar 

  10. 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(9):3577–3593

    Article  PubMed  CAS  Google Scholar 

  11. 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(1):165–174

    Article  PubMed  CAS  Google Scholar 

  12. Reichel A (2009) Addressing central nervous system (CNS) penetration in drug discovery: basics and implications of the evolving new concept. Chem Biodivers 6(11):2030–2049

    Article  PubMed  CAS  Google Scholar 

  13. Gibaldi M (1969) Effect of mode of administration on drug distribution in a two-compartment open system. J Pharm Sci 58(3):327–331

    Article  PubMed  CAS  Google Scholar 

  14. Padowski J, Pollack G (in press) 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

  15. Hammond EJ, Perchalski RJ, Villarreal HJ, Wilder BJ (1982) In vivo uptake of valproic acid into brain. Brain Res 240(1):195–198

    Article  PubMed  CAS  Google Scholar 

  16. Hariton C, Ciesielski L, Simler S, Valli M, Jadot G, Gobaille S, Mesdjian E, Mandel P (1984) Distribution of sodium valproate and GABA metabolism in CNS of the rat. Biopharm Drug Dispos 5(4):409–414

    Article  PubMed  CAS  Google Scholar 

  17. Nau H, Loscher W (1982) Valproic acid: brain and plasma levels of the drug and its metabolites, anticonvulsant effects and gamma-aminobutyric acid (GABA) metabolism in the mouse. J Pharmacol Exp Ther 220(3):654–659

    PubMed  CAS  Google Scholar 

  18. Stapleton SL, Thompson PA, Ou CN, Berg SL, McGuffey L, Gibson B, Blaney SM (2008) Plasma and cerebrospinal fluid pharmacokinetics of valproic acid after oral administration in non-human primates. Cancer Chemother Pharmacol 61(4):647–652

    Article  PubMed  CAS  Google Scholar 

  19. Dickinson RG, Harland RC, Ilias AM, Rodgers RM, Kaufman SN, Lynn RK, Gerber N (1979) Disposition of valproic acid in the rat: dose-dependent metabolism, distribution, enterohepatic recirculation and choleretic effect. J Pharmacol Exp Ther 211(3):583–595

    PubMed  CAS  Google Scholar 

  20. Dickinson RG, Hooper WD, Eadie MJ (1984) pH-dependent rearrangement of the biosynthetic ester glucuronide of valproic acid to beta-glucuronidase-resistant forms. Drug Metab Dispos 12(2):247–252

    PubMed  CAS  Google Scholar 

  21. Pollack GM, Brouwer KL (1991) Physiologic and metabolic influences on enterohepatic recirculation: simulations based upon the disposition of valproic acid in the rat. J Pharmacokinet Biopharm 19(2):189–225

    Article  PubMed  CAS  Google Scholar 

  22. Golden PL, Brouwer KR, Pollack GM (1993) Assessment of valproic acid serum-cerebrospinal fluid transport by microdialysis. Pharm Res 10(12):1765–1771

    Article  PubMed  CAS  Google Scholar 

  23. Allerheiligen SR (2010) Next-generation model-based drug discovery and development: quantitative and systems pharmacology. Clin Pharmacol Ther 88(1):135–137

    Article  PubMed  CAS  Google Scholar 

  24. Chan KK, Gibaldi M (1985) Assessment of drug absorption after oral administration. J Pharm Sci 74(4):388–393

    Article  PubMed  CAS  Google Scholar 

  25. 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(2):128–134

    Article  PubMed  CAS  Google Scholar 

  26. Liu MJ, Pollack GM (1994) Pharmacokinetics and pharmacodynamics of valproate analogues in rats. IV. Anticonvulsant action and neurotoxicity of octanoic acid, cyclohexanecarboxylic acid, and 1-methyl-1-cyclohexanecarboxylic acid. Epilepsia 35(1):234–243

    Article  PubMed  CAS  Google Scholar 

  27. Liu MJ, Pollack GM (1993) Pharmacokinetics and pharmacodynamics of valproate analogs in rats. II. Pharmacokinetics of octanoic acid, cyclohexanecarboxylic acid, and 1-methyl-1-cyclohexanecarboxylic acid. Biopharm Drug Dispos 14(4):325–339

    Article  PubMed  CAS  Google Scholar 

  28. Haberer LJ, Pollack GM (1994) Disposition and protein binding of valproic acid in the developing rat. Drug Metab Dispos 22(1):113–119

    PubMed  CAS  Google Scholar 

  29. Liu MJ, Brouwer KL, Pollack GM (1992) Pharmacokinetics and pharmacodynamics of valproate analogs in rats III Pharmacokinetics of valproic acid, cyclohexanecarboxylic acid, and 1-methyl-1-cyclohexanecarboxylic acid in the bile-exteriorized rat. Drug Metab Dispos 20(6):810–815

    PubMed  Google Scholar 

  30. 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(18):1427–1437

    Article  PubMed  CAS  Google Scholar 

  31. Wright AW, Dickinson RG (2004) Abolition of valproate-derived choleresis in the Mrp2 transporter-deficient rat. J Pharmacol Exp Ther 310(2):584–588

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported in part by the National Institutes of Health, National Institute of General Medical Sciences (Grant GM61191), Eli Lilly and Company, and NIEHS T32-ES007126.

Author information

Author notes

  1. Jeannie M. Padowski

    Present address: Department of Radiology, University of Washington, Box 357115, 1959 NE Pacific Street, AA-010A, Seattle, WA, 98195, USA

Authors and Affiliations

  1. Curriculum in Toxicology, School of Medicine and Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Jeannie M. Padowski & Gary M. Pollack

  2. College of Pharmacy, Washington State University, 105F Wegner Hall, PO Box 646510, Pullman, WA, 99164, USA

    Gary M. Pollack

Authors
  1. Jeannie M. Padowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gary M. Pollack
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gary M. Pollack.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Padowski, J.M., Pollack, G.M. The influence of distributional kinetics into a peripheral compartment on the pharmacokinetics of substrate partitioning between blood and brain tissue. J Pharmacokinet Pharmacodyn 38, 743–767 (2011). https://doi.org/10.1007/s10928-011-9218-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10928-011-9218-0

Keywords

Search

Navigation