Abstract
Purpose
The selective protein tyrosine kinase inhibitor, imatinib, inhibits the growth of glioma cells in preclinical models, but its poor brain distribution limits its efficacy in patients. P-glycoprotein (P-gp, rodent Mdr1a/1b or Abcb1a/1b) and Breast cancer resistance protein (rodent Bcrp1 or Abcg2) were suggested to restrict the delivery of imatinib to the brain. This study evaluates the effect of administering selective inhibitors of these transporters together with imatinib on the systemic and cerebral disposition of imatinib in mice.
Materials and Methods
Wild-type, Mdr1a/1b(−/−) and Bcrp1(−/−) mice were given imatinib intravenously, either alone, or with valspodar, zosuquidar (P-gp inhibitors), or elacridar (a P-gp and Bcrp1 inhibitor). The blood and brain concentrations of [14C]imatinib and its radioactive metabolites were determined.
Results
The blockade of P-gp by valspodar or zosuquidar (>3 mg/kg) enhanced the brain uptake of imatinib (∼4-fold) in wild-type mice, but not that of its metabolites. Blockade of both P-gp and Bcrp1 by elacridar (>3 mg/kg) produced significantly greater brain penetration of imatinib (9.3-fold) and its metabolites (2.8-fold). In contrast, only the lack of P-gp enhanced imatinib brain penetration (6.4-fold) in knockout mice. These results of brain uptake correlated reasonably well with those obtained previously by our group using in situ brain perfusion.
Conclusions
Imatinib and its metabolites penetrate into the brain poorly and their penetration is limited by P-gp and (probably) Bcrp1. Administering imatinib together with P-gp (and Bcrp1) transporter inhibitors such as elacridar may improve the delivery of imatinib to the brain, making it potentially more effective against malignant gliomas.
Notes
Bihorel S, Camenisch G, Lemaire M, et al. Influence of Breast Cancer Resistance Protein (Abcg2) and P-glycoprotein (Abcb1a/1b) on imatinib mesylate (Gleevec®) transport across the mouse blood–brain barrier. Submitted for publication.
Wiegand H and Pfaar U, unpublished data
Abbreviations
- ABC:
-
ATP-binding cassette
- BB ratio:
-
Blood/brain concentration ratio
- BBB:
-
Blood–brain barrier
- BCRP:
-
Breast cancer resistance protein
- CNS:
-
Central nervous system
- K net :
-
Net transport coefficient
- MG:
-
Malignant glioma
- P-gp:
-
P-glycoprotein
- SD:
-
Standard deviation
References
E. Buchdunger, T. O’Reilly, and J. Wood. Pharmacology of imatinib (STI571). Eur. J. Cancer. 38:S28–S36 (2002).
M. H. Cohen, J. R. Johnson, and R. Pazdur. U.S. Food and Drug Administration Drug Approval Summary: conversion of imatinib mesylate (STI571; Gleevec) tablets from accelerated approval to full approval. Clin. Cancer Res. 11:12–19 (2005).
R. Dagher, M. Cohen, G. Williams, M. Rothmann, J. Gobburu, G. Robbie, A. Rahman, G. Chen, A. Staten, D. Griebel, and R. Pazdur. Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin. Cancer Res. 8:3034–3038 (2002).
T. Kilic, J. A. Alberta, P. R. Zdunek, M. Acar, P. Iannarelli, T. O’Reilly, E. Buchdunger, P. M. Black, and C. D. Stiles. Intracranial inhibition of platelet-derived growth factor-mediated glioblastoma cell growth by an orally active kinase inhibitor of the 2-phenylaminopyrimidine class. Cancer Res. 60:5143–5150 (2000).
E. Raymond, A. Brandes, A. Van Oosterom, C. Dittrich, P. Fumoleau, B. Coudert, C. Twelves, C. De Balincourt, D. Lacombe, and M. Van Den Bent. Multicentre phase II study of imatinib mesylate in patients with recurrent glioblastoma: an EORTC: NDDG/BTG Intergroup Study. ASCO Meeting Abstracts. 22:1501 (2004).
P. Y. Wen, W. K. Yung, K. Hess, S. Silbermann, M. Hayes, D. Schiff, F. Lieberman, T. F. Cloughesy, L. M. DeAngelis, S. M. Chang, L. Junck, H. A. Fine, K. Fink, H. I. Robins, J. J. Raizer, L. E. Abrey, M. P. Mehta, E. A. Maher, P. M. Black, J. Kuhn, R. Capdeville, R. S. Kaplan, A. Murgo, C. Stiles, and M. D. Prados. Phase I study of STI571 (Gleevec) for patients with recurrent malignant gliomas and meningiomas (NABTC 99-08). Proc. Am. Soc. Clin. Oncol. 21: (2002).
H. Dai, P. Marbach, M. Lemaire, M. Hayes, and W. F. Elmquist. Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux. J. Pharmacol. Exp. Ther. 304:1085–1092 (2003).
P. Le Coutre, K. A. Kreuzer, S. Pursche, M. Bonin, T. Leopold, G. Baskaynak, B. Dorken, G. Ehninger, O. Ottmann, A. Jenke, M. Bornhauser, and E. Schleyer. Pharmacokinetics and cellular uptake of imatinib and its main metabolite CGP74588. Cancer Chemother. Pharmacol. 53:313–323 (2004).
K. Neville, R. A. Parise, P. Thompson, A. Aleksic, M. J. Egorin, F. M. Balis, L. McGuffey, C. McCully, S. L. Berg, and S. M. Blaney. Plasma and cerebrospinal fluid pharmacokinetics of imatinib after administration to nonhuman primates. Clin. Cancer Res. 10:2525–2529 (2004).
D. A. Reardon, M. J. Egorin, J. A. Quinn, J. N. Rich, Sr., I. Gururangan, J. J. Vredenburgh, A. Desjardins, S. Sathornsumetee, J. M. Provenzale, J. E. Herndon, J. M. Dowell, M. A. Badruddoja, R. E. McLendon, T. F. Lagattuta, K. P. Kicielinski, G. Dresemann, J. H. Sampson, A. H. Friedman, A. J. Salvado, and H. S. Friedman. Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. J. Clin. Oncol. 23:9359–9368 (2005).
D. J. Begley. Delivery of therapeutic agents to the central nervous system: the problems and the possibilities. Pharmacol. Ther. 104:29–45 (2004).
W. M. Pardridge. The blood–brain barrier: bottleneck in brain drug development. NeuroRx. 2:3–14 (2005).
C. L. Graff, and G. M. Pollack. Drug transport at the blood–brain barrier and the choroid plexus. Curr. Drug Metab. 5:95–108 (2004).
E. C. de Lange. Potential role of ABC transporters as a detoxification system at the blood–CSF barrier. Adv. Drug Deliv. Rev. 56:1793–1809 (2004).
H. Kusuhara, and Y. Sugiyama. Efflux transport systems for organic anions and cations at the blood–CSF barrier. Adv. Drug Deliv. Rev. 56:1741–1763 (2004).
H. Kusuhara and Y. Sugiyama. Active efflux across the blood–brain barrier: role of the solute carrier family. NeuroRx. 2:73–85 (2005).
W. Loscher, and H. Potschka. Blood–brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx. 2:86–98 (2005).
H. Burger, H. van Tol, A. W. Boersma, M. Brok, E. A. Wiemer, G. Stoter, and K. Nooter. Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump. Blood 104:2940–2942 (2004).
Hamada, H. Miyano, H. Watanabe, and H. Saito. Interaction of imatinib mesilate with human P-glycoprotein. J. Pharmacol. Exp. Ther. 307:824–828 (2003).
P. J. Houghton, G. S. Germain, F. C. Harwood, J. D. Schuetz, C. F. Stewart, E. Buchdunger, and P. Traxler. Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro. Cancer Res. 64:2333–2337 (2004).
P. Breedveld, D. Pluim, G. Cipriani, P. Wielinga, O. van Tellingen, A. H. Schinkel, and J. H. Schellens. 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. 65:2577–2582 (2005).
Y. Takasato, S. I. Rapoport, and Q. R. Smith. An in situ brain perfusion technique to study cerebrovascular transport in the rat. Am. J. Physiol. 247:484–493 (1984).
C. Dagenais, C. Rousselle, G. M. Pollack, and J. M. Scherrmann. Development of an in situ mouse brain perfusion model and its application to mdr1a P-glycoprotein-deficient mice. J. Cereb. Blood Flow Metab. 20:381–386 (2000).
Q. R. Smith, and J. M. Walker. A review of blood–brain barrier transport techniques. The blood–brain barrier—Biology and Research Protocols, Vol. 89, Humana, Totowa, NJ, 2003, pp. 193–208.
U. Bickel. How to measure drug transport across the blood–brain barrier. NeuroRx. 2:15–26 (2005).
R. L. Shepard, J. Cao, J. J. Starling, and A. H. Dantzig. Modulation of P-glycoprotein but not MRP1- or BCRP-mediated drug resistance by LY335979. Int. J. Cancer. 103:121–125 (2003).
H. L. Tai. Technology evaluation: Valspodar, Novartis AG. Curr. Opin. Mol. Ther. 2:459–467 (2000).
M. de Bruin, K. Miyake, T. Litman, R. Robey, and S. E. Bates. Reversal of resistance by GF120918 in cell lines expressing the ABC half-transporter, MXR. Cancer Lett. 146:117–126 (1999).
S. Desrayaud. Rôle de la glycoprotéine P dans la distribution cérébrale d’un dérivé de la cyclosporine, le SDZ PSC833, Université, René Descartes, Paris, France, 1997.
D. W. Everett, J. E. Foley, S. M. Singhvi, S. H. Weinstein, and S. J. Warrington. High-performance liquid chromatographic method for the radiometric determination of [14C] bucromarone in human plasma utilizing non-radiolabeled bucromarone as an internal standard. J. Chromatogr. 487:365–373 (1989).
S. P. Khor, and M. Mayersohn. Potential error in the measurement of tissue to blood distribution coefficients in physiological pharmacokinetic modeling. Residual tissue blood. I. Theoretical considerations. Drug Metab. Dispos. 19:478–485 (1991).
S. Cisternino, F. Bourasset, Y. Archimbaud, D. Semiond, G. Sanderink, and J. M. Scherrmann. Nonlinear accumulation in the brain of the new taxoid TXD258 following saturation of P-glycoprotein at the blood–brain barrier in mice and rats. Br. J. Pharmacol. 138:1367–1375 (2003).
L. B. Lan, J. T. Dalton, and E. G. Schuetz. Mdr1 limits CYP3A metabolism in vivo. Mol. Pharmacol. 58:863–869 (2000).
E. G. Schuetz, D. R. Umbenhauer, K. Yasuda, C. Brimer, L. Nguyen, M. V. Relling, J. D. Schuetz, and A. H. Schinkel. Altered expression of hepatic cytochromes P-450 in mice deficient in one or more mdr1 genes. Mol. Pharmacol. 57:188–197 (2000).
B. Peng, P. Lloyd, and H. Schran. Clinical pharmacokinetics of imatinib. Clin. Pharmacokinet. 44:879–894 (2005).
E. F. Choo, B. Leake, C. Wandel, H. Imamura, A. J. Wood, G. R. Wilkinson, and R. B. Kim. Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metab Dispos. 28:655–660 (2000).
E. M. Kemper, A. E. van Zandbergen, C. Cleypool, H. A. Mos, W. Boogerd, J. H. Beijnen, and O. van Tellingen. Increased penetration of paclitaxel into the brain by inhibition of P-Glycoprotein. Clin. Cancer Res. 9:2849–2855 (2003).
U. Mayer, E. Wagenaar, B. Dorobek, J. H. Beijnen, P. Borst, and A. H. Schinkel. Full blockade of intestinal P-glycoprotein and extensive inhibition of blood–brain barrier P-glycoprotein by oral treatment of mice with PSC833. J. Clin. Invest. 100:2430–2436 (1997).
H. P. Gschwind, U. Pfaar, F. Waldmeier, M. Zollinger, C. Sayer, P. Zbinden, M. Hayes, R. Pokorny, M. Seiberling, M. Ben-Am, B. Peng, and G. Gross. Metabolism and disposition of imatinib mesylate in healthy volunteers. Drug Metab. Dispos. 33:1503–1512 (2005).
Acknowledgments
We thank Dr. Yves Auberson (Novartis Institutes for Biomedical Research) for providing zosuquidar and elacridar, Dr. Rachael Profit and Dr Owen Parkes for editing the English text. This work was supported by Novartis Pharma AG contract (Novartis-INSERM n° 03035A10) to Dr. Sébastien Bihorel and Dr. Jean-Michel Scherrmann.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bihorel, S., Camenisch, G., Lemaire, M. et al. Modulation of the Brain Distribution of Imatinib and its Metabolites in Mice by Valspodar, Zosuquidar and Elacridar. Pharm Res 24, 1720–1728 (2007). https://doi.org/10.1007/s11095-007-9278-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11095-007-9278-4