This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kemper, E. M. Articles by van Tellingen, O. Search for Related Content PubMed PubMed Citation Articles by Kemper, E. M. Articles by van Tellingen, O.

Increased Penetration of Paclitaxel into the Brain by Inhibition of P-Glycoprotein¹

The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, the Netherlands [E. M. K., A. E. v. Z., C. C., W. B., J. H. B., O. v. T.]; GlaxoSmithKline BV, 3705 LZ Zeist, the Netherlands [H. A. M.]; Department of Neurology, Slotervaart Hospital, 1066 EC Amsterdam, the Netherlands [W. B.]; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, 1066 EC Amsterdam, the Netherlands [J. H. B.]; and Division of Drug Toxicology, Faculty of Pharmaceutical Sciences, Utrecht University, 3584 CA Utrecht, the Netherlands [J. H. B.]

P-Glycoprotein (Pgp) in the blood-brain barrier limits the uptake of substrate drugs into the brain. We have determined the efficacy of several (putative) inhibitors of Pgp (cyclosporin A, PSC833, GF120918, and Cremophor EL) on the penetration of paclitaxel into the mouse brain. Pgp inhibitors were administered p.o. before i.v. paclitaxel. Plasma and tissues were collected at 1, 4, 8, and 24 h and analyzed for paclitaxel by high-performance liquid chromatography. Pgp knockout mice were used as reference for complete blockade of Pgp and to determine the selectivity of Pgp inhibitors on the pharmacokinetics of paclitaxel. Cremophor EL had no effect at all. Increased brain uptake was observed with cyclosporin A (3-fold), PSC833 (6.5-fold), and GF120918 (5-fold), although the levels were lower than that observed in Pgp knockout mice (11-fold increase). Both cyclosporin A and PSC833 also markedly increased the plasma levels of paclitaxel in contrast to GF120918. Obviously, cyclosporin A and PSC833 markedly inhibited several elimination pathways of paclitaxel, whereas the reduced clearance of paclitaxel by GF120918 was most probably related to the inhibition of Pgp alone. After further optimization of the dose and schedule of GF120918, we could achieve paclitaxel brain levels of about 80–90% of those reached in Pgp knockout mice. It is warranted to test paclitaxel in combination with GF120918 in experimental brain tumor models and in clinical trials.

This article has been cited by other articles:

				D. S. Miller, B. Bauer, and A. M. S. Hartz Modulation of P-Glycoprotein at the Blood-Brain Barrier: Opportunities to Improve Central Nervous System Pharmacotherapy Pharmacol. Rev., June 1, 2008; 60(2): 196 - 209. [Abstract] [Full Text] [PDF]

				N. A. de Vries, J. Zhao, E. Kroon, T. Buckle, J. H. Beijnen, and O. van Tellingen P-Glycoprotein and Breast Cancer Resistance Protein: Two Dominant Transporters Working Together in Limiting the Brain Penetration of Topotecan Clin. Cancer Res., November 1, 2007; 13(21): 6440 - 6449. [Abstract] [Full Text] [PDF]

				S. Marchetti, R. Mazzanti, J. H. Beijnen, and J. H. M. Schellens Concise Review: Clinical Relevance of Drug Drug and Herb Drug Interactions Mediated by the ABC Transporter ABCB1 (MDR1, P-glycoprotein) Oncologist, August 1, 2007; 12(8): 927 - 941. [Abstract] [Full Text] [PDF]

				J. F. Deeken and W. Loscher The Blood-Brain Barrier and Cancer: Transporters, Treatment, and Trojan Horses Clin. Cancer Res., March 15, 2007; 13(6): 1663 - 1674. [Abstract] [Full Text] [PDF]

				M. G. Belinsky, P. Guo, K. Lee, F. Zhou, E. Kotova, A. Grinberg, H. Westphal, I. Shchaveleva, A. Klein-Szanto, J. M. Gallo, et al. Multidrug Resistance Protein 4 Protects Bone Marrow, Thymus, Spleen, and Intestine from Nucleotide Analogue-Induced Damage Cancer Res., January 1, 2007; 67(1): 262 - 268. [Abstract] [Full Text] [PDF]

				A. Yokota, S. Kimura, S. Masuda, E. Ashihara, J. Kuroda, K. Sato, Y. Kamitsuji, E. Kawata, Y. Deguchi, Y. Urasaki, et al. INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity Blood, January 1, 2007; 109(1): 306 - 314. [Abstract] [Full Text] [PDF]

				E. F. Choo, D. Kurnik, M. Muszkat, T. Ohkubo, S. D. Shay, J. N. Higginbotham, H. Glaeser, R. B. Kim, A. J. J. Wood, and G. R. Wilkinson Differential in Vivo Sensitivity to Inhibition of P-glycoprotein Located in Lymphocytes, Testes, and the Blood-Brain Barrier J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1012 - 1018. [Abstract] [Full Text] [PDF]

				P. Hsiao, L. Sasongko, J. M. Link, D. A. Mankoff, M. Muzi, A. C. Collier, and J. D. Unadkat Verapamil P-glycoprotein Transport across the Rat Blood-Brain Barrier: Cyclosporine, a Concentration Inhibition Analysis, and Comparison with Human Data J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 704 - 710. [Abstract] [Full Text] [PDF]

				P. Breedveld, D. Pluim, G. Cipriani, P. Wielinga, O. van Tellingen, A. H. Schinkel, and J. H.M. 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., April 1, 2005; 65(7): 2577 - 2582. [Abstract] [Full Text] [PDF]

				B. Bauer, A. M. S. Hartz, G. Fricker, and D. S. Miller Modulation of p-Glycoprotein Transport Function at the Blood-Brain Barrier Experimental Biology and Medicine, February 1, 2005; 230(2): 118 - 127. [Abstract] [Full Text] [PDF]

				N. D. Doolittle, L. E. Abrey, W. A. Bleyer, S. Brem, T. P. Davis, P. Dore-Duffy, L. R. Drewes, W. A. Hall, J. M. Hoffman, A. Korfel, et al. New Frontiers in Translational Research in Neuro-oncology and the Blood-Brain Barrier: Report of the Tenth Annual Blood-Brain Barrier Disruption Consortium Meeting Clin. Cancer Res., January 15, 2005; 11(2): 421 - 428. [Abstract] [Full Text] [PDF]