Skip to main content

Advertisement

SpringerLink
Log in

The Role of Size and Charge for Blood–Brain Barrier Permeation of Drugs and Fatty Acids

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

The lipid bilayer is the diffusion barrier of biological membranes. Highly protective membranes such as the blood–brain barrier (BBB) are reinforced by ABC transporters such as P-glycoprotein (MDR1, ABCB1) and multidrug resistance associated proteins (MRPs, ABCCs). The transporters bind their substrates in the cytosolic lipid bilayer leaflet before they reach the cytosol and flip them to the outer leaflet. The large majority of drugs targeted to the central nervous system (CNS) are intrinsic substrates of these transporters. Whether an intrinsic substrate can cross the BBB depends on whether passive influx is higher than active efflux. In this paper, we show that passive influx can be estimated quantitatively on the basis of Stokesian diffusion, taking into account the ionization constant and the cross-sectional area of the molecule in its membrane bond conformation, as well as the lateral packing density of the membrane. Active efflux by ABC transporters was measured. The calculated net flux is in excellent agreement with experimental results. The approach is exemplified with several drugs and fatty acid analogs. It shows that compounds with small cross-sectional areas (A D < 70 Å2) and/or intermediate or low charge exhibit higher passive influx than efflux and, therefore, cross the BBB despite being intrinsic substrates. Large (A D > 70 Å2) or highly charged compounds show higher efflux than influx. They cannot cross the BBB and are, thus, apparent substrates for ABC transporters. The strict size and charge limitation for BBB permeation results from the synergistic interaction between passive influx and active efflux.

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

Notes

  1. Equation 3 applies in principle to spherical particles. The diffusion coefficient of elongated molecules with a small cross-sectional area may, therefore, be somewhat overestimated.

References

  • Aanismaa, P., & Seelig, A. (2007). P-glycoprotein kinetics measured in plasma membrane vesicles and living cells. Biochemistry, 46, 3394–3404.

    Article  PubMed  CAS  Google Scholar 

  • Al-Shawi, M. K., Polar, M. K., Omote, H., & Figler, R. A. (2003). Transition state analysis of the coupling of drug transport to ATP hydrolysis by P-glycoprotein. Journal of Biological Chemistry, 278, 52629–52640.

    Article  PubMed  CAS  Google Scholar 

  • Altenbach, C., & Seelig, J. (1985). Binding of the lipophilic cation tetraphenylphosphonium to phosphatidylcholine membranes. Biochimica Et Biophysica Acta, 818, 410.

    Article  CAS  Google Scholar 

  • Ambudkar, S. V. (1998). Drug-stimulatable ATPase activity in crude membranes of human MDR1-transfected mammalian cells. Methods in Enzymology, 292, 504–514.

    PubMed  CAS  Google Scholar 

  • Bassolino-Klimas, D., Alper, H. E., & Stouch, T. R. (1993). Solute diffusion in lipid bilayer membranes: An atomic level study by molecular dynamics simulation. Biochemistry, 32, 12624–12637.

    Article  PubMed  CAS  Google Scholar 

  • Begley, D. J. (2004). ABC transporters and the blood-brain barrier. Current Pharmaceutical Design, 10, 1295–1312.

    Article  PubMed  CAS  Google Scholar 

  • Beschiaschvili, G., & Seelig, J. (1992). Peptide binding to lipid bilayers. Nonclassical hydrophobic effect and membrane-induced pK shifts. Biochemistry, 31, 10044–10053.

    Article  PubMed  CAS  Google Scholar 

  • Boguslavsky, V., Rebecchi, M., Morris, A. J., Jhon, D. Y., Rhee, S. G., & McLaughlin, S. (1994). Effect of monolayer surface pressure on the activities of phosphoinositide-specific phospholipase C-beta 1, -gamma 1, and -delta 1. Biochemistry, 33, 3032–3037.

    Article  PubMed  CAS  Google Scholar 

  • Burton, P. S., Goodwin, J. T., Vidmar, T. J., & Amore, B. M. (2002). Predicting drug absorption: How nature made it a difficult problem. Journal of Pharmacology and Experimental Therapeutics, 303, 889–895.

    Article  PubMed  CAS  Google Scholar 

  • Cistola, D. P., Atkinson, D., Hamilton, J. A., & Small, D. M. (1986). Phase behavior and bilayer properties of fatty acids: Hydrated 1:1 acid-soaps. Biochemistry, 25, 2804–2812.

    Article  PubMed  CAS  Google Scholar 

  • Didziapetris, R., Japertas, P., Avdeef, A., & Petrauskas, A. (2003). Classification analysis of P-glycoprotein substrate specificity. Journal of Drug Targeting, 11, 391–406.

    Article  PubMed  CAS  Google Scholar 

  • Finkelstein, A. (1987). Water movement through lipid bilayers, pores, and plasma membranes. Theory and reality. New York: Wiley.

    Google Scholar 

  • Fischer, H., Gottschlich, R., & Seelig, A. (1998). Blood–brain barrier permeation: molecular parameters governing passive diffusion. Journal of Membrane Biology, 165, 201–211.

    Article  PubMed  CAS  Google Scholar 

  • Gatlik-Landwojtowicz, E., Aanismaa, P., & Seelig, A. (2004). The rate of P-glycoprotein activation depends on the metabolic state of the cell. Biochemistry, 43, 14840–14851.

    Article  PubMed  CAS  Google Scholar 

  • Gatlik-Landwojtowicz, E., Aanismaa, P., & Seelig, A. (2006). Quantification and characterization of P-glycoprotein-substrate interactions. Biochemistry, 45, 3020–3032.

    Article  PubMed  CAS  Google Scholar 

  • Gerebtzoff, G., Li-Blatter, X., Fischer, H., Frentzel, A., & Seelig, A. (2004). Halogenation of drugs enhances membrane binding and permeation. ChemBioChem, 5, 676–684.

    Article  PubMed  CAS  Google Scholar 

  • Gerebtzoff, G., & Seelig, A. (2006). In silico prediction of blood–brain barrier permeation using the calculated molecular cross-sectional area as main parameter. Journal of Chemical Information and Modeling, 46, 2638–2650.

    Article  PubMed  CAS  Google Scholar 

  • Golin, J., Ambudkar, S. V., Gottesman, M. M., Habib, A. D., Sczepanski, J., Ziccardi, W., et al. (2003). Studies with novel Pdr5p substrates demonstrate a strong size dependence for xenobiotic efflux. Journal of Biological Chemistry, 278, 5963–5969.

    Article  PubMed  CAS  Google Scholar 

  • Hamilton, J. A. (1998). Fatty acid transport: Difficult or easy? Journal of Lipid Research, 39, 467–481.

    PubMed  CAS  Google Scholar 

  • Hamilton, J. A., & Kamp, F. (1999). How are free fatty acids transported in membranes? Is it by proteins or by free diffusion through the lipids? Diabetes, 48, 2255–2269.

    Article  PubMed  CAS  Google Scholar 

  • Higgins, C. F., & Linton, K. J. (2004). The ATP switch model for ABC transporters. Natural Structural Molecular Biology, 11, 918–926.

    Article  CAS  Google Scholar 

  • Kamp, F., & Hamilton, J. A. (1992). pH gradients across phospholipid membranes caused by fast flip-flop of un-ionized fatty acids. Proceedings of the National Academy of Sciences of the United States of America, 89, 11367–11370.

    Article  PubMed  CAS  Google Scholar 

  • Landwojtowicz, E., Nervi, P., & Seelig, A. (2002). Real-time monitoring of P-glycoprotein activation in living cells. Biochemistry, 41, 8050–8057.

    Article  PubMed  CAS  Google Scholar 

  • Litman, T., Nielsen, D., Skovsgaard, T., Zeuthen, T., & Stein, W. D. (1997a). ATPase activity of P-glycoprotein related to emergence of drug resistance in Ehrlich ascites tumor cell lines. Biochimica Et Biophysica Acta, 1361, 147–158.

    PubMed  CAS  Google Scholar 

  • Litman, T., Zeuthen, T., Skovsgaard, T., & Stein, W. D. (1997b). Competitive, non-competitive and cooperative interactions between substrates of P-glycoprotein as measured by its ATPase activity. Biochimica Et Biophysica Acta, 1361, 169–176.

    PubMed  CAS  Google Scholar 

  • Litman, T., Zeuthen, T., Skovsgaard, T., & Stein, W. D. (1997c). Structure-activity relationships of P-glycoprotein interacting drugs: Kinetic characterization of their effects on ATPase activity. Biochimica Et Biophysica Acta, 1361, 159–168.

    PubMed  CAS  Google Scholar 

  • Mealey, K. L., Bentjen, S. A., Gay, J. M., & Cantor, G. H. (2001). Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics, 11, 727–733.

    Article  PubMed  CAS  Google Scholar 

  • Meier, M., Blatter, X. L., Seelig, A., & Seelig, J. (2006). Interaction of verapamil with lipid membranes and P-glycoprotein: connecting thermodynamics and membrane structure with functional activity. Biophysical Journal, 91, 2943–2955.

    Article  PubMed  CAS  Google Scholar 

  • Ogawa, K., Yumoto, R., Hamada, N., Nagai, J., & Takano, M. (2006). Interaction of valproic acid and carbapenem antibiotics with multidrug resistance-associated proteins in rat erythrocyte membranes. Epilepsy Research, 71, 76–87.

    Article  PubMed  CAS  Google Scholar 

  • Omote, H., & Al-Shawi, M. K. (2002). A novel electron paramagnetic resonance approach to determine the mechanism of drug transport by P-glycoprotein. Journal of Biological Chemistry, 277, 45688–45694.

    Article  PubMed  CAS  Google Scholar 

  • Omote, H., & Al-Shawi, M. K. (2006). Interaction of transported drugs with the lipid bilayer and P-glycoprotein through a solvation exchange mechanism. Biophysical Journal, 90, 4046–4059.

    Article  PubMed  CAS  Google Scholar 

  • Pani, L., Kuzmin, A., Diana, M., De Montis, G., Gessa, G. L., & Rossetti, Z. L. (1990). Calcium receptor antagonists modify cocaine effects in the central nervous system differently. European Journal of Pharmacology, 190, 217–221.

    Article  PubMed  CAS  Google Scholar 

  • Pauletti, G. M., Okumu, F. W., & Borchardt, R. T. (1997). Effect of size and charge on the passive diffusion of peptides across Caco-2 cell monolayers via the paracellular pathway. Pharmaceutical Research, 14, 164–168.

    Article  PubMed  CAS  Google Scholar 

  • Saparov, S. M., Antonenko, Y. N., & Pohl, P. (2006). A new model of weak acid permeation through membranes revisited: Does Overton still rule? Biophysical Journal, 90, L86–L88.

    Article  PubMed  CAS  Google Scholar 

  • Schinkel, A. H., Wagenaar, E., van Deemter, L., Mol, C. A., & Borst, P. (1995). Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. Journal of Clinical Investigation, 96, 1698–1705.

    Article  PubMed  CAS  Google Scholar 

  • Seelig, A. (1987). Local anesthetics and pressure: A comparison of dibucaine binding to lipid monolayers and bilayers. Biochimica Et Biophysica Acta, 899, 196–204.

    Article  PubMed  CAS  Google Scholar 

  • Seelig, A. (1998). A general pattern for substrate recognition by P-glycoprotein. European Journal of Biochemistry, 251, 252–261.

    Article  PubMed  CAS  Google Scholar 

  • Seelig, A. (2006). Unraveling membrane-mediated substrate-transporter interactions. Biophysical Journal, 90, 3825–3826.

    Article  PubMed  CAS  Google Scholar 

  • Seelig, A., Blatter, X. L., & Wohnsland, F. (2000). Substrate recognition by P-glycoprotein and the multidrug resistance-associated protein MRP1: A comparison. International Journal of Clinical Physical Therapy, 38, 111–121.

    CAS  Google Scholar 

  • Seelig, A., & Gatlik-Landwojtowicz, E. (2005). Inhibitors of multidrug efflux transporters: Their membrane and protein interactions. Mini Reviews in Medicinal Chemistry, 5, 135–151.

    PubMed  CAS  Google Scholar 

  • Seelig, A., & Gerebtzoff, G. (2006). Enhancement of drug absorption by noncharged detergents through membrane and P-glycoprotein binding. Expert Opinion on Drug Metabolism & Toxicology, 2, 733–752.

    Article  CAS  Google Scholar 

  • Seelig, A., Gottschlich, R., & Devant, R. M. (1994). A method to determine the ability of drugs to diffuse through the blood–brain barrier. Proceedings of the National Academy of Sciences of the United States of America, 91, 68–72.

    Article  PubMed  CAS  Google Scholar 

  • Seelig, A., & Landwojtowicz, E. (2000). Structure–activity relationship of P-glycoprotein substrates and modifiers. European Journal of Pharmaceutical Sciences, 12, 31–40.

    Article  PubMed  CAS  Google Scholar 

  • Seelig, A., & Seelig, J. (2002). Membrane structure, in encyclopedia of physical science and technology (9th ed., pp. 355–367). New York: Academic.

    Google Scholar 

  • Seelig, J., & Seelig, A. (1980). Lipid conformation in model membranes and biological membranes. Quarterly Reviews of Biophysics, 13, 19–61.

    Article  PubMed  CAS  Google Scholar 

  • Thuerauf, N., & Fromm, M. F. (2006). The role of the transporter P-glycoprotein for disposition and effects of centrally acting drugs and for the pathogenesis of CNS diseases. European Archives of Psychiatry and Clinical Neuroscience, 256, 281–286.

    Article  PubMed  Google Scholar 

  • Varma, M. V., Sateesh, K., & Panchagnula, R. (2005). Functional role of P-glycoprotein in limiting intestinal absorption of drugs: Contribution of passive permeability to P-glycoprotein mediated efflux transport. Molecular Pharmacology, 2, 12–21.

    Article  CAS  Google Scholar 

  • Watts, A., & Poile, T. W. (1986). Direct determination by 2H-NMR of the ionization state of phospholipids and of a local anaesthetic at the membrane surface. Biochimica Et Biophysica Acta, 861, 368–372.

    Article  PubMed  CAS  Google Scholar 

  • Zhao, Y. L., Du, J., Kanazawa, H., Sugawara, A., Takagi, K., Kitaichi, K., et al. (2002). Effect of endotoxin on doxorubicin transport across blood–brain barrier and P-glycoprotein function in mice. European Journal of Pharmacology, 445, 115–123.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

I am grateful to Dr. Grégori Gerebtzoff for modeling the compounds in Fig. 3 and to Dr. Renate Reiter and Dr. Andreas Zumbühl for carefully reading the ms. This work was supported by the Swiss National Science Foundation, grant no. 3100-107793.

Author information

Authors and Affiliations

  1. Biophysical Chemistry, Biozentrum, University of Basel, Klingelbergstrasse 70, Basel, Switzerland

    Anna Seelig

Authors
  1. Anna Seelig
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anna Seelig.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Seelig, A. The Role of Size and Charge for Blood–Brain Barrier Permeation of Drugs and Fatty Acids. J Mol Neurosci 33, 32–41 (2007). https://doi.org/10.1007/s12031-007-0055-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-007-0055-y

Keywords

Search

Navigation