Advertisement

The AAPS Journal

, Volume 15, Issue 4, pp 1082–1090 | Cite as

Effects of Selected OATP and/or ABC Transporter Inhibitors on the Brain and Whole-Body Distribution of Glyburide

  • Nicolas Tournier
  • Wadad Saba
  • Salvatore Cisternino
  • Marie-Anne Peyronneau
  • Annelaure Damont
  • Sébastien Goutal
  • Albertine Dubois
  • Frédéric Dollé
  • Jean-Michel Scherrmann
  • Héric Valette
  • Bertrand Kuhnast
  • Michel Bottlaender
Research Article

Abstract

Glyburide (glibenclamide, GLB) is a widely prescribed antidiabetic with potential beneficial effects in central nervous system injury and diseases. In vitro studies show that GLB is a substrate of organic anion transporting polypeptide (OATP) and ATP-binding cassette (ABC) transporter families, which may influence GLB distribution and pharmacokinetics in vivo. In the present study, we used [11C]GLB positron emission tomography (PET) imaging to non-invasively observe the distribution of GLB at a non-saturating tracer dose in baboons. The role of OATP and P-glycoprotein (P-gp) in [11C]GLB whole-body distribution, plasma kinetics, and metabolism was assessed using the OATP inhibitor rifampicin and the dual OATP/P-gp inhibitor cyclosporine. Finally, we used in situ brain perfusion in mice to pinpoint the effect of ABC transporters on GLB transport at the blood–brain barrier (BBB). PET revealed the critical role of OATP on liver [11C]GLB uptake and its subsequent impact on [11C]GLB metabolism and plasma clearance. OATP-mediated uptake also occurred in the myocardium and kidney parenchyma but not the brain. The inhibition of P-gp in addition to OATP did not further influence [11C]GLB tissue and plasma kinetics. At the BBB, the inhibition of both P-gp and breast cancer resistance protein (BCRP) was necessary to demonstrate the role of ABC transporters in limiting GLB brain uptake. This study demonstrates that GLB distribution, metabolism, and elimination are greatly dependent on OATP activity, the first step in GLB hepatic clearance. Conversely, P-gp, BCRP, and probably multidrug resistance protein 4 work in synergy to limit GLB brain uptake.

KEY WORDS

ABC transporters blood–brain barrier glyburide organic anion transporting polypeptide positron emission tomography 

Notes

ACKNOWLEDGMENTS

We thank Maria Smirnova, Vincent Brulon, and Amandine Grelier, who contributed to the research. Statistical analyses were performed by Dr. Marcel Debray. The English text was edited by Dr. S. Rasika. Salvatore Cisternino received a grant from the Commissariat à l'énergie atomique et aux énergies alternatives and the Assistance Publique des Hôpitaux de Paris.

Conflict of Interest

The authors have no conflict of interest to declare.

References

  1. 1.
    Schattling B, Steinbach K, Thies E, Kruse M, Menigoz A, Ufer F, et al. TRPM4 cation channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med. 2012;18:1805–11.PubMedCrossRefGoogle Scholar
  2. 2.
    Simard JM, Woo SK, Schwartzbauer GT, Gerzanich V. Sulfonylurea receptor 1 in central nervous system injury: a focused review. J Cereb Blood Flow Metab. 2012;32:1699–717.PubMedCrossRefGoogle Scholar
  3. 3.
    Gedeon C, Behravan J, Koren G, Piquette-Miller M. Transport of glyburide by placental ABC transporters: implications in fetal drug exposure. Placenta. 2006;27:1096–102.PubMedCrossRefGoogle Scholar
  4. 4.
    Cygalova LH, Hofman J, Ceckova M, Staud F. Transplacental pharmacokinetics of glyburide, rhodamine 123, and BODIPY FL prazosin: effect of drug efflux transporters and lipid solubility. J Pharmacol Exp Ther. 2009;331:1118–25.PubMedCrossRefGoogle Scholar
  5. 5.
    Zhou L, Naraharisetti SB, Wang H, Unadkat JD, Hebert MF, Mao Q. The breast cancer resistance protein (Bcrp1/Abcg2) limits fetal distribution of glyburide in the pregnant mouse: an Obstetric-Fetal Pharmacology Research Unit Network and University of Washington Specialized Center of Research Study. Mol Pharmacol. 2008;73:949–59.PubMedCrossRefGoogle Scholar
  6. 6.
    Pollex E, Lubetsky A, Koren G. The role of placental breast cancer resistance protein in the efflux of glyburide across the human placenta. Placenta. 2008;29:743–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Hemauer SJ, Patrikeeva SL, Nanovskaya TN, Hankins GDV, Ahmed MS. Role of human placental apical membrane transporters in the efflux of glyburide, rosiglitazone, and metformin. Am J Obstet Gynecol. 2010;202:383.e1–7.CrossRefGoogle Scholar
  8. 8.
    Gedeon C, Anger G, Piquette-Miller M, Koren G. Breast cancer resistance protein: mediating the trans-placental transfer of glyburide across the human placenta. Placenta. 2008;29:39–43.PubMedCrossRefGoogle Scholar
  9. 9.
    Golstein PE, Boom A, van Geffel J, Jacobs P, Masereel B, Beauwens R. P-glycoprotein inhibition by glibenclamide and related compounds. Pflugers Arch. 1999;437:652–60.PubMedCrossRefGoogle Scholar
  10. 10.
    Satoh H, Yamashita F, Tsujimoto M, Murakami H, Koyabu N, Ohtani H, et al. Citrus juices inhibit the function of human organic anion-transporting polypeptide OATP-B. Drug Metab Dispos. 2005;33:518–23.PubMedCrossRefGoogle Scholar
  11. 11.
    Koenen A, Köck K, Keiser M, Siegmund W, Kroemer HK, Grube M. Steroid hormones specifically modify the activity of organic anion transporting polypeptides. Eur J Pharm Sci. 2012;47:774–80.PubMedCrossRefGoogle Scholar
  12. 12.
    König J, Müller F, Fromm MF. Transporters and drug–drug interactions: important determinants of drug disposition and effects. Pharmacol Rev. 2013;65:944–66.PubMedCrossRefGoogle Scholar
  13. 13.
    Vavricka SR, Van Montfoort J, Ha HR, Meier PJ, Fattinger K. Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. Hepatology. 2002;36:164–72.PubMedCrossRefGoogle Scholar
  14. 14.
    Zheng HX, Huang Y, Frassetto LA, Benet LZ. Elucidating rifampin's inducing and inhibiting effects on glyburide pharmacokinetics and blood glucose in healthy volunteers: unmasking the differential effects of enzyme induction and transporter inhibition for a drug and its primary metabolite. Clin Pharmacol Ther. 2009;85:78–85.PubMedCrossRefGoogle Scholar
  15. 15.
    Shawahna R, Uchida Y, Declèves X, Ohtsuki S, Yousif S, Dauchy S, et al. Transcriptomic and quantitative proteomic analysis of transporters and drug metabolizing enzymes in freshly isolated human brain microvessels. Mol Pharm. 2011;8:1332–41.PubMedCrossRefGoogle Scholar
  16. 16.
    Agarwal S, Uchida Y, Mittapalli RK, Sane R, Terasaki T, Elmquist WF. Quantitative proteomics of transporter expression in brain capillary endothelial cells isolated from P-glycoprotein (P-gp), breast cancer resistance protein (Bcrp), and P-gp/Bcrp knockout mice. Drug Metab Dispos. 2012;40:1164–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Kuhnast B, Damont A, Tournier N, Saba W, Valette H, Bottlaender M, et al. Radiosynthesis of [C-11]glyburide for in vivo imaging of BCRP function with PET. J Label Compounds Radiopharm. 2011;54 Suppl 1:S262.Google Scholar
  18. 18.
    Tournier N, Chevillard L, Megarbane B, Pirnay S, Scherrmann J-M, Declèves X. Interaction of drugs of abuse and maintenance treatments with human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2). Int J Neuropsychopharmacol. 2010;13:905–15.PubMedCrossRefGoogle Scholar
  19. 19.
    Cisternino S, Mercier C, Bourasset F, Roux F, Scherrmann J-M. Expression, up-regulation, and transport activity of the multidrug-resistance protein Abcg2 at the mouse blood–brain barrier. Cancer Res. 2004;64:3296–301.PubMedCrossRefGoogle Scholar
  20. 20.
    Sane R, Agarwal S, Mittapalli RK, Elmquist WF. Saturable active efflux by P-glycoprotein and breast cancer resistance protein at the blood–brain barrier leads to nonlinear distribution of elacridar to the central nervous system. J Pharmacol Exp Ther. 2013;345:111–24.PubMedCrossRefGoogle Scholar
  21. 21.
    Cattelotte J, André P, Ouellet M, Bourasset F, Scherrmann J-M, Cisternino S. In situ mouse carotid perfusion model: glucose and cholesterol transport in the eye and brain. J Cereb Blood Flow Metab. 2008;28:1449–59.PubMedCrossRefGoogle Scholar
  22. 22.
    Mease K, Sane R, Podila L, Taub ME. Differential selectivity of efflux transporter inhibitors in Caco-2 and MDCK-MDR1 monolayers: a strategy to assess the interaction of a new chemical entity with P-gp, BCRP, and MRP2. J Pharm Sci. 2012;101:1888–97.PubMedCrossRefGoogle Scholar
  23. 23.
    Xie M, Rich TC, Scheitrum C, Conti M, Richter W. Inactivation of multidrug resistance proteins disrupts both cellular extrusion and intracellular degradation of cAMP. Mol Pharmacol. 2011;80:281–93.PubMedCrossRefGoogle Scholar
  24. 24.
    Zhou L, Naraharisetti SB, Liu L, Wang H, Lin YS, Isoherranen N, et al. Contributions of human cytochrome P450 enzymes to glyburide metabolism. Biopharm Drug Dispos. 2010;31:228–42.PubMedGoogle Scholar
  25. 25.
    Amundsen R, Åsberg A, Ohm IK, Christensen H. Cyclosporine A- and tacrolimus-mediated inhibition of CYP3A4 and CYP3A5 in vitro. Drug Metab Dispos. 2012;40:655–61.PubMedCrossRefGoogle Scholar
  26. 26.
    Li X-Q, Andersson TB, Ahlström M, Weidolf L. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos. 2004;32:821–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Lau YY, Okochi H, Huang Y, Benet LZ. Pharmacokinetics of atorvastatin and its hydroxy metabolites in rats and the effects of concomitant rifampicin single doses: relevance of first-pass effect from hepatic uptake transporters, and intestinal and hepatic metabolism. Drug Metab Dispos. 2006;34:1175–81.PubMedCrossRefGoogle Scholar
  28. 28.
    De Vries NA, Zhao J, Kroon E, Buckle T, Beijnen JH, van Tellingen O. P-glycoprotein and breast cancer resistance protein: two dominant transporters working together in limiting the brain penetration of topotecan. Clin Cancer Res. 2007;13:6440–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Lin F, Marchetti S, Pluim D, Iusuf D, Mazzanti R, Schellens JHM, et al. Abcc4 together with Abcb1 and Abcg2 form a robust co-operative drug efflux system that restricts the brain entry of camptothecin analogs. Clin Cancer Res. 2013;19:2084–95.PubMedCrossRefGoogle Scholar
  30. 30.
    Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, et al. Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug–drug interactions. J Med Chem. 2012;55:4740–63.PubMedCrossRefGoogle Scholar
  31. 31.
    Breedveld P, Pluim D, Cipriani G, Wielinga P, van Tellingen O, Schinkel AH, et al. The effect of Bcrp1 (Abcg2) on the in vivo pharmacokinetics and brain penetration of imatinib mesylate (Gleevec): implications for the use of breast cancer resistance protein and P-glycoprotein inhibitors to enable the brain penetration of imatinib in patients. Cancer Res. 2005;65:2577–82.PubMedCrossRefGoogle Scholar
  32. 32.
    Pearson JG, Antal EJ, Raehl CL, Gorsch HK, Craig WA, Albert KS, et al. Pharmacokinetic disposition of 14C-glyburide in patients with varying renal function. Clin Pharmacol Ther. 1986;39:318–24.PubMedCrossRefGoogle Scholar
  33. 33.
    Nishimura M, Naito S. Tissue-specific mRNA expression profiles of human solute carrier transporter superfamilies. Drug Metab Pharmacokinet. 2008;23:22–44.PubMedCrossRefGoogle Scholar
  34. 34.
    Grube M, Köck K, Oswald S, Draber K, Meissner K, Eckel L, et al. Organic anion transporting polypeptide 2B1 is a high-affinity transporter for atorvastatin and is expressed in the human heart. Clin Pharmacol Ther. 2006;80:607–20.PubMedCrossRefGoogle Scholar
  35. 35.
    Juurlink DN, Gomes T, Shah BR, Mamdani MM. Adverse cardiovascular events during treatment with glyburide (glibenclamide) or gliclazide in a high-risk population. Diabet Med. 2012;29:1524–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Hoshi Y, Uchida Y, Tachikawa M, Inoue T, Ohtsuki S, Terasaki T. Quantitative atlas of blood–brain barrier transporters, receptors, and tight junction proteins in rats and common marmoset. J Pharm Sci. 2013. doi: 10.1002/jps.23575.PubMedGoogle Scholar
  37. 37.
    Clark DE. In silico prediction of blood–brain barrier permeation. Drug Discov Today. 2003;8:927–33.PubMedCrossRefGoogle Scholar
  38. 38.
    Nanovskaya TN, Patrikeeva S, Hemauer S, Fokina V, Mattison D, Hankins GD, et al. Effect of albumin on transplacental transfer and distribution of rosiglitazone and glyburide. J Matern Fetal Neonatal Med. 2008;21:197–207.PubMedCrossRefGoogle Scholar
  39. 39.
    Takashima T, Kitamura S, Wada Y, Tanaka M, Shigihara Y, Ishii H, et al. PET imaging-based evaluation of hepatobiliary transport in humans with (15R)-11C-TIC-Me. J Nucl Med. 2012;53:741–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Leonhardt M, Keiser M, Oswald S, Kühn J, Jia J, Grube M, et al. Hepatic uptake of the magnetic resonance imaging contrast agent Gd-EOB-DTPA: role of human organic anion transporters. Drug Metab Dispos. 2010;38:1024–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Bruderer S, Aänismaa P, Homery M-C, Häusler S, Landskroner K, Sidharta PN, et al. Effect of cyclosporine and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist. AAPS J. 2012;14:68–78.PubMedCrossRefGoogle Scholar
  42. 42.
    De Bruyn T, Fattah S, Stieger B, Augustijns P, Annaert P. Sodium fluorescein is a probe substrate for hepatic drug transport mediated by OATP1B1 and OATP1B3. J Pharm Sci. 2011;100:5018–30.PubMedCrossRefGoogle Scholar
  43. 43.
    Picard N, Levoir L, Lamoureux F, Yee SW, Giacomini KM, Marquet P. Interaction of sirolimus and everolimus with hepatic and intestinal organic anion-transporting polypeptide transporters. Xenobiotica. 2011;41:752–7.PubMedCrossRefGoogle Scholar
  44. 44.
    König J, Glaeser H, Keiser M, Mandery K, Klotz U, Fromm MF. Role of organic anion-transporting polypeptides for cellular mesalazine (5-aminosalicylic acid) uptake. Drug Metab Dispos. 2011;39:1097–102.PubMedCrossRefGoogle Scholar
  45. 45.
    Obaidat A, Roth M, Hagenbuch B. The expression and function of organic anion transporting polypeptides in normal tissues and in cancer. Annu Rev Pharmacol Toxicol. 2012;52:135–51.PubMedCrossRefGoogle Scholar
  46. 46.
    Nishimura M, Naito S. Tissue-specific mRNA expression profiles of human ATP-binding cassette and solute carrier transporter superfamilies. Drug Metab Pharmacokinet. 2005;20:452–77.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2013

Authors and Affiliations

  • Nicolas Tournier
    • 1
  • Wadad Saba
    • 1
  • Salvatore Cisternino
    • 1
    • 2
    • 3
  • Marie-Anne Peyronneau
    • 1
  • Annelaure Damont
    • 1
  • Sébastien Goutal
    • 1
  • Albertine Dubois
    • 1
  • Frédéric Dollé
    • 1
  • Jean-Michel Scherrmann
    • 2
    • 3
  • Héric Valette
    • 1
  • Bertrand Kuhnast
    • 1
  • Michel Bottlaender
    • 1
  1. 1.CEA, DSV, I2BM, Service Hospitalier Frédéric JoliotOrsayFrance
  2. 2.INSERM U705, CNRS UMR8206, Faculté de Pharmacie, Université Paris Descartes, Sorbonne Paris CitéUniversité Paris DiderotParisFrance
  3. 3.Assistance Publique–Hôpitaux de ParisParisFrance

Personalised recommendations