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

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.107.018374v1 36/4/695    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 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 Polli, J. W. Articles by Serabjit-Singh, C. J. Search for Related Content PubMed PubMed Citation Articles by Polli, J. W. Articles by Serabjit-Singh, C. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH

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

Preclinical Drug Metabolism and Pharmacokinetics (J.W.P., J.E.H., K.A.H., S.C., M.J.O., K.L.O., L.S.J.W., C.J.S.S.) and Clinical Pharmacokinetics Modeling and Simulation (K.M.K.), GlaxoSmithKline, Research Triangle Park, North Carolina

Lapatinib [N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine, GW572016, Tykerb] is a tyrosine kinase inhibitor approved for use in combination with capecitabine to treat advanced or metastatic breast cancers overexpressing HER2 (ErbB2). In this work we investigated the role of efflux and uptake transporters in lapatinib disposition and drug interactions. In vitro studies evaluated whether lapatinib is a substrate for efflux transporters or an inhibitor of efflux/uptake transporters. In vivo studies included whole-body autoradiography and an evaluation of the role of efflux transporters on the intestinal absorption and brain penetration of lapatinib using chemical or genetic knockout animals. Lapatinib is a substrate for the efflux transporters P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Furthermore, lapatinib is an inhibitor (IC₅₀ values 0.025–5 µM) of Pgp, BCRP, and organic anion transporting polypeptide 1B1 (a hepatic uptake transporter). In contrast, lapatinib yielded little inhibition on renal transporters (organic anion transporters, organic cation transporters, and uric acid transporter). In vivo studies demonstrated that brain concentrations of lapatinib were low and influenced by efflux transporters at the blood-brain barrier. In contrast, systemic exposure of lapatinib after oral dosing was unchanged when efflux by Pgp and BCRP was absent from the gastrointestinal tract. These in vitro and in vivo preclinical investigations provide a mechanistic basis for elucidating clinical drug interactions.

This article has been cited by other articles:

				B. Leyland-Jones Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Central Nervous System Metastases J. Clin. Oncol., November 1, 2009; 27(31): 5278 - 5286. [Abstract] [Full Text] [PDF]

				H. A. Burris III, C. W. Taylor, S. F. Jones, K. M. Koch, M. J. Versola, N. Arya, R. A. Fleming, D. A. Smith, L. Pandite, N. Spector, et al. A Phase I and Pharmacokinetic Study of Oral Lapatinib Administered Once or Twice Daily in Patients with Solid Malignancies Clin. Cancer Res., November 1, 2009; 15(21): 6702 - 6708. [Abstract] [Full Text] [PDF]

				T. Pienkowski and C. C. Zielinski Trastuzumab treatment in patients with breast cancer and metastatic CNS disease Ann. Onc., August 28, 2009; (2009) mdp353v1. [Abstract] [Full Text] [PDF]

				K. M. Koch, N. J. Reddy, R. B. Cohen, N. L. Lewis, B. Whitehead, K. Mackay, A. Stead, A. P. Beelen, and L. D. Lewis Effects of Food on the Relative Bioavailability of Lapatinib in Cancer Patients J. Clin. Oncol., March 10, 2009; 27(8): 1191 - 1196. [Abstract] [Full Text] [PDF]

				S. Shukla, R. W. Robey, S. E. Bates, and S. V. Ambudkar Sunitinib (Sutent, SU11248), a Small-Molecule Receptor Tyrosine Kinase Inhibitor, Blocks Function of the ATP-Binding Cassette (ABC) Transporters P-Glycoprotein (ABCB1) and ABCG2 Drug Metab. Dispos., February 1, 2009; 37(2): 359 - 365. [Abstract] [Full Text] [PDF]

				J. W. Polli, K. L. Olson, J. P. Chism, L. St. John-Williams, R. L. Yeager, S. M. Woodard, V. Otto, S. Castellino, and V. E. Demby An Unexpected Synergist Role of P-Glycoprotein and Breast Cancer Resistance Protein on the Central Nervous System Penetration of the Tyrosine Kinase Inhibitor Lapatinib (N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016) Drug Metab. Dispos., February 1, 2009; 37(2): 439 - 442. [Abstract] [Full Text] [PDF]

				J. R. Molina, S. H. Kaufmann, J. M. Reid, S. D. Rubin, M. Galvez-Peralta, R. Friedman, K. S. Flatten, K. M. Koch, T. M. Gilmer, R. J. Mullin, et al. Evaluation of Lapatinib and Topotecan Combination Therapy: Tissue Culture, Murine Xenograft, and Phase I Clinical Trial Data Clin. Cancer Res., December 1, 2008; 14(23): 7900 - 7908. [Abstract] [Full Text] [PDF]

				C.-l. Dai, A. K. Tiwari, C.-P. Wu, X.-d. Su, S.-R. Wang, D.-g. Liu, C. R. Ashby Jr., Y. Huang, R. W. Robey, Y.-j. Liang, et al. Lapatinib (Tykerb, GW572016) Reverses Multidrug Resistance in Cancer Cells by Inhibiting the Activity of ATP-Binding Cassette Subfamily B Member 1 and G Member 2 Cancer Res., October 1, 2008; 68(19): 7905 - 7914. [Abstract] [Full Text] [PDF]