Skip to main content

Advertisement

SpringerLink
Log in

The Antiepileptic Drug Topiramate is a Substrate for Human P-glycoprotein but Not Multidrug Resistance Proteins

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

Resistance to antiepileptic drugs (AEDs) is the major problem in the treatment of epilepsy. One of the candidate mechanisms of pharmacoresistance is the limitation of AED access to the seizure focus by overexpression of efflux transporters, including P-glycoprotein (Pgp) and multidrug resistance proteins (MRPs). In this respect, it is important to know which AEDs are substrates for such drug transporters in humans.

Methods

In the present study, we used polarized kidney cell lines (LLC, MDCK) transfected with human drug transporters (Pgp, MRP1, MRP2 or MRP5) to evaluate whether the AED topiramate is a substrate for any of these transporters. Known Pgp and MRP substrates were used for comparison.

Results

Basolateral-to-apical transport of topiramate, which could be counteracted with the Pgp inhibitor, tariquidar, was determined in Pgp overexpressing LLC cells, whereas topiramate was not transported by any of the MRPs. A comparison with previous experiments in the same transport assay showed that topiramate exhibited the most pronounced Pgp-mediated efflux transport among the AEDS that have been studied as yet.

Conclusions

Thus, these data indicate that brain levels of topiramate may be affected by overexpression of Pgp as determined in patients with intractable epilepsy.

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

Similar content being viewed by others

REFERENCES

  1. van Passel L, Arif H, Hirsch LJ. Topiramate for the treatment of epilepsy and other nervous system disorders. Expert Rev Neurother. 2006;6:19–31.

    Article  PubMed  Google Scholar 

  2. Hitiris N, Brodie MJ. Modern antiepileptic drugs: guidelines and beyond. Curr Opin Neurol. 2006;19:175–80.

    PubMed  Google Scholar 

  3. Schmidt D, Löscher W. Drug resistance in epilepsy: putative neurobiologic and clinical mechanisms. Epilepsia 2005;46:858–77.

    Article  CAS  PubMed  Google Scholar 

  4. Löscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci. 2005;6:591–602.

    Article  PubMed  Google Scholar 

  5. Remy S, Beck H. Molecular and cellular mechanisms of pharmacoresistance in epilepsy. Brain 2006;129:18–35.

    Article  PubMed  Google Scholar 

  6. Löscher W. Animal models of drug-refractory epilepsy. In: Pitkänen A, Schwartzkroin PA, Moshe SL, editors. Models of seizures and epilepsy. San Diego: Elsevier; 2006. p. 551–66.

    Chapter  Google Scholar 

  7. Potschka H, Volk HA, Löscher W. Pharmacoresistance and expression of multidrug transporter P-glycoprotein in kindled rats. NeuroReport. 2004;19:1657–61.

    Article  Google Scholar 

  8. Kwan P, Brodie MJ. Potential role of drug transporters in the pathogenesis of medically intractable epilepsy. Epilepsia 2005;46:224–35.

    Article  CAS  PubMed  Google Scholar 

  9. Luna-Tortós C, Fedrowitz M, Löscher W. Several major antiepileptic drugs are substrates for human P-glycoprotein. Neuropharmacology 2008;55:1364–75.

    Article  PubMed  Google Scholar 

  10. Baltes S, Gastens AM, Fedrowitz M, Potschka H, Kaever V, Löscher W. Differences in the transport of the antiepileptic drugs phenytoin, levetiracetam and carbamazepine by human and mouse P-glycoprotein. Neuropharmacology 2007;52:333–46.

    Article  CAS  PubMed  Google Scholar 

  11. Baltes S, Fedrowitz M, Tortos CL, Potschka H, Löscher W. Valproic acid is not a substrate for P-glycoprotein or multidrug resistance proteins 1 and 2 in a number of in vitro and in vivo transport assays. J Pharmacol Exp Ther. 2007;320:331–43.

    Article  CAS  PubMed  Google Scholar 

  12. Rambeck B, Jürgens UH, May TW, Pannek HW, Behne F, Ebner A, et al. Comparison of brain extracellular fluid, brain tissue, cerebrospinal fluid, and serum concentrations of antiepileptic drugs measured intraoperatively in patients with intractable epilepsy. Epilepsia 2006;47:681–94.

    Article  CAS  PubMed  Google Scholar 

  13. Olson DP, Taylor BJ, Ivy SP. Detection of MRP functional activity: calcein AM but not BCECF AM as a Multidrug Resistance-related Protein (MRP1) substrate. Cytometry 2001;46:105–13.

    Article  CAS  PubMed  Google Scholar 

  14. Dogan AL, Legrand O, Faussat AM, Perrot JY, Marie JP. Evaluation and comparison of MRP1 activity with three fluorescent dyes and three modulators in leukemic cell lines. Leuk Res. 2004;28:619–22.

    Article  CAS  PubMed  Google Scholar 

  15. Szakacs G, Jakab K, Antal F, Sarkadi B. Diagnostics of multidrug resistance in cancer. Pathol Oncol Res. 1998;4:251–7.

    Article  CAS  PubMed  Google Scholar 

  16. McAleer MA, Breen MA, White NL, Matthews N. pABC11 (also known as MOAT-C and MRP5), a member of the ABC family of proteins, has anion transporter activity but does not confer multidrug resistance when overexpressed in human embryonic kidney 293 cells. J Biol Chem. 1999;274:23541–8.

    Article  CAS  PubMed  Google Scholar 

  17. Pratt S, Chen V, Perry WI III, Starling JJ, Dantzig AH. Kinetic validation of the use of carboxydichlorofluorescein as a drug surrogate for MRP5-mediated transport. Eur J Pharm Sci. 2006;27:524–32.

    Article  CAS  PubMed  Google Scholar 

  18. Schinkel AH, Wagenaar E, Mol CA, van Deemter L. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest. 1996;97:2517–24.

    Article  CAS  PubMed  Google Scholar 

  19. Yamazaki M, Neway WE, Ohe T, Chen I, Rowe JF, Hochman JH, et al. In vitro substrate identification studies for p-glycoprotein-mediated transport: species difference and predictability of in vivo results. J Pharmacol Exp Ther. 2001;296:723–35.

    CAS  PubMed  Google Scholar 

  20. Hsiao P, Bui T, Ho RJ, Unadkat JD. In vitro-to-in vivo prediction of P-glycoprotein-based drug interactions at the human and rodent blood-brain barrier. Drug Metab Dispos. 2008;36:481–4.

    Article  CAS  PubMed  Google Scholar 

  21. Kühnle M, Egger M, Müller C, Mahringer A, Bernhardt G, Fricker G, et al. Potent and selective inhibitors of breast cancer resistance protein (ABCG2) derived from the p-glycoprotein (ABCB1) modulator tariquidar. J Med Chem. 2009;52:1190–7.

    Article  PubMed  Google Scholar 

  22. Sills GJ, Kwan P, Butler E, de Lange EC, van den Berg DJ, Brodie MJ. P-glycoprotein-mediated efflux of antiepileptic drugs: preliminary studies in mdr1a knockout mice. Epilepsy Behav. 2002;3:427–32.

    Article  PubMed  Google Scholar 

  23. Takeuchi T, Yoshitomi S, Higuchi T, Ikemoto K, Niwa S, Ebihara T, et al. Establishment and characterization of the transformants stably-expressing MDR1 derived from various animal species in LLC-PK1. Pharm Res. 2006;23:1460–72.

    Article  CAS  PubMed  Google Scholar 

  24. Kim IW, Booth-Genthe C, Ambudkar SV. Relationship between drugs and functional activity of various mammalian P-glycoproteins (ABCB1). Mini Rev Med Chem. 2008;8:193–200.

    Article  CAS  PubMed  Google Scholar 

  25. Crowe A, Teoh YK. Limited P-glycoprotein mediated efflux for anti-epileptic drugs. J Drug Target. 2006;14:291–300.

    Article  CAS  PubMed  Google Scholar 

  26. Wang Q, Strab R, Kardos P, Ferguson C, Li J, Owen A, et al. Application and limitation of inhibitors in drug-transporter interactions studies. Int J Pharm. 2008;356:12–8.

    Article  CAS  PubMed  Google Scholar 

  27. Lentz KA, Polli JW, Wring SA, Humphreys JE, Polli JE. Influence of passive permeability on apparent P-glycoprotein kinetics. Pharm Res. 2000;17:1456–60.

    Article  CAS  PubMed  Google Scholar 

  28. Santaguida S, Janigro D, Hossain M, Oby E, Rapp E, Cucullo L. Side by side comparison between dynamic versus static models of blood-brain barrier in vitro: a permeability study. Brain Res. 2006;1109:1–13.

    Article  CAS  PubMed  Google Scholar 

  29. Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7:41–53.

    Article  CAS  PubMed  Google Scholar 

  30. Goh LB, Spears KJ, Yao D, Ayrton A, Morgan P, Roland WC, et al. Endogenous drug transporters in in vitro and in vivo models for the prediction of drug disposition in man. Biochem Pharmacol. 2002;64:1569–78.

    Article  CAS  PubMed  Google Scholar 

  31. Borst P, Evers R, Kool M, Wijnholds J. A family of drug transporters: the multidrug resistance- associated proteins. J Natl Cancer Inst. 2000;92:1295–302.

    Article  CAS  PubMed  Google Scholar 

  32. Borst P, de Wolf C, van de Wetering K. Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Arch. 2007;453:661–73.

    Article  CAS  PubMed  Google Scholar 

  33. Dombrowski SM, Desai SY, Marroni M, Cucullo L, Goodrich K, Bingaman W, et al. Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy. Epilepsia 2001;42:1501–6.

    Article  CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGEMENTS

We thank Prof. Piet Borst (The Netherlands Cancer Institute) and his group for kindly providing us with the cell lines used in this study. The study was supported by a grant (Lo 274/10-1) from the Deutsche Forschungsgemeinschaft (Bonn, Germany). Carlos Luna-Tortós receives a Ph.D. scholarship from the DAAD (German Academic Exchange Service; Bonn, Germany).

Author information

Authors and Affiliations

  1. Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, Bünteweg 17, 30559, Hannover, Germany

    Carlos Luna-Tortós & Wolfgang Löscher

  2. Center for Systems Neuroscience, Hannover, Germany

    Carlos Luna-Tortós & Wolfgang Löscher

  3. Pharmacological Laboratory of the Society for Epilepsy Research, Epilepsy Center Bethel, Bielefeld, Germany

    Bernhard Rambeck & Uwe H. Jürgens

Authors
  1. Carlos Luna-Tortós
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bernhard Rambeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Uwe H. Jürgens
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wolfgang Löscher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wolfgang Löscher.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Luna-Tortós, C., Rambeck, B., Jürgens, U.H. et al. The Antiepileptic Drug Topiramate is a Substrate for Human P-glycoprotein but Not Multidrug Resistance Proteins. Pharm Res 26, 2464–2470 (2009). https://doi.org/10.1007/s11095-009-9961-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-009-9961-8

KEY WORDS

Search

Navigation