QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.055574v1 307/2/824    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map 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 Hamada, A. Articles by Saito, H. Search for Related Content PubMed PubMed Citation Articles by Hamada, A. Articles by Saito, H. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB IMATINIB MESYLATE

ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Interaction of Imatinib Mesilate with Human P-Glycoprotein

Department of Pharmacy, Kumamoto University Hospital, Honjo, Kumamoto, Japan

The interaction of imatinib mesilate with P-glycoprotein (P-gp) was examined using pig kidney epithelial LLC-PK1 cells versus L-MDR1 cells, which overexpress human P-gp on the apical membrane. The basal-to-apical transport of imatinib mesilate in L-MDR1 cells significantly exceeded that in the parental LLCPK1 cells. The intracellular accumulation of imatinib mesilate after its basal application to LLC-PK1 and L-MDR1 cells was 35% and 15%, respectively. A P-gp modulator, cyclosporin A, inhibited the basal-to-apical transport in L-MDR1 cells. The intracellular accumulation of imatinib mesilate in L-MDR1 cells was also increased by cyclosporin A. The rhodamine 123 efflux assay showed that the efflux of rhodamine 123 in K562/DXR cells, which overexpress human P-gp, could be blocked markedly by imatinib mesilate in a dose-dependent fashion. The K_i values for the inhibition of P-gp function by cyclosporin A and imatinib mesilate were estimated to be 6.1 and 18.3 µM, respectively, using a calcein-AM efflux assay. These observations demonstrate that imatinib mesilate is a substrate as well as a modulator of human P-gp, suggesting that imatinib mesilate drug interactions may occur via P-gp. It is necessary to consider the pharmacokinetic and pharmacodynamic interactions of imatinib mesilate with other drugs via P-gp.

Address correspondence to: Hideyuki Saito, Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Kumamoto 860-8556, Japan. E-mail: saitohide{at}fc.kuh.kumamoto-u.ac.jp

This article has been cited by other articles:

				L. Zhou, K. Schmidt, F. R. Nelson, V. Zelesky, M. D. Troutman, and B. Feng The Effect of Breast Cancer Resistance Protein and P-Glycoprotein on the Brain Penetration of Flavopiridol, Imatinib Mesylate (Gleevec), Prazosin, and 2-Methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)propanoic Acid (PF-407288) in Mice Drug Metab. Dispos., May 1, 2009; 37(5): 946 - 955. [Abstract] [Full Text] [PDF]

				J. S. Lagas, R. A.B. van Waterschoot, V. A.C.J. van Tilburg, M. J. Hillebrand, N. Lankheet, H. Rosing, J. H. Beijnen, and A. H. Schinkel Brain Accumulation of Dasatinib Is Restricted by P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) and Can Be Enhanced by Elacridar Treatment Clin. Cancer Res., April 1, 2009; 15(7): 2344 - 2351. [Abstract] [Full Text] [PDF]

				S. Hu, R. M. Franke, K. K. Filipski, C. Hu, S. J. Orwick, E. A. de Bruijn, H. Burger, S. D. Baker, and A. Sparreboom Interaction of Imatinib with Human Organic Ion Carriers Clin. Cancer Res., May 15, 2008; 14(10): 3141 - 3148. [Abstract] [Full Text] [PDF]

				J. W. Polli, J. E. Humphreys, K. A. Harmon, S. Castellino, M. J. O'Mara, K. L. Olson, L. St. John-Williams, K. M. Koch, and C. J. Serabjit-Singh The Role of Efflux and Uptake Transporters in N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, Lapatinib) Disposition and Drug Interactions Drug Metab. Dispos., April 1, 2008; 36(4): 695 - 701. [Abstract] [Full Text] [PDF]

				M. M. Shareef, B. Brown, S. Shajahan, S. Sathishkumar, S. M. Arnold, M. Mohiuddin, M. M. Ahmed, and P. M. Spring Lack of P-Glycoprotein Expression by Low-Dose Fractionated Radiation Results from Loss of Nuclear Factor-{kappa}B and NF-Y Activation in Oral Carcinoma Cells Mol. Cancer Res., January 1, 2008; 6(1): 89 - 98. [Abstract] [Full Text] [PDF]

				A. V. Boddy, J. Sludden, M. J. Griffin, C. Garner, J. Kendrick, P. Mistry, C. Dutreix, D. R. Newell, and S. G. O'Brien Pharmacokinetic Investigation of Imatinib Using Accelerator Mass Spectrometry in Patients with Chronic Myeloid Leukemia Clin. Cancer Res., July 15, 2007; 13(14): 4164 - 4169. [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]

				F. Rossi, I. Ehlers, V. Agosti, N. D. Socci, A. Viale, G. Sommer, Y. Yozgat, K. Manova, C. R. Antonescu, and P. Besmer Oncogenic Kit signaling and therapeutic intervention in a mouse model of gastrointestinal stromal tumor PNAS, August 22, 2006; 103(34): 12843 - 12848. [Abstract] [Full Text] [PDF]

				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 II, et al. Phase II Study of Imatinib Mesylate Plus Hydroxyurea in Adults With Recurrent Glioblastoma Multiforme J. Clin. Oncol., December 20, 2005; 23(36): 9359 - 9368. [Abstract] [Full Text] [PDF]

				D. White, V. Saunders, A. B. Lyons, S. Branford, A. Grigg, L. B. To, and T. Hughes In vitro sensitivity to imatinib-induced inhibition of ABL kinase activity is predictive of molecular response in patients with de novo CML Blood, October 1, 2005; 106(7): 2520 - 2526. [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]

				M. Deininger, E. Buchdunger, and B. J. Druker The development of imatinib as a therapeutic agent for chronic myeloid leukemia Blood, April 1, 2005; 105(7): 2640 - 2653. [Abstract] [Full Text] [PDF]

				J. Thomas, L. Wang, R. E. Clark, and M. Pirmohamed Active transport of imatinib into and out of cells: implications for drug resistance Blood, December 1, 2004; 104(12): 3739 - 3745. [Abstract] [Full Text] [PDF]