Nilotinib concentration in cell lines and primary CD34(+) chronic myeloid leukemia cells is not mediated by active uptake or efflux by major drug transporters

Leukemia. 2009 Nov;23(11):1999-2006. doi: 10.1038/leu.2009.166. Epub 2009 Aug 27.

Abstract

Imatinib mesylate and nilotinib are highly effective at eradicating the majority of chronic myeloid leukemia (CML) cells; however, neither agent induces apoptosis of primitive CML CD34(+) cells. One possible explanation is that CD34(+) cells do not accumulate sufficient intracellular drug levels because of either inadequate active uptake or increased efflux. To determine the interaction of nilotinib with major clinically implicated drug transporters, we analyzed their interactions with MDR1 (ABCB1), MRP1 (ABCC1), ABCG2 (BCRP) and human organic cation transporter (hOCT)1 in CML cell lines and primitive (CD34(+)) primary CML cells. Nilotinib is neither dependent on active import by hOCT1, nor effluxed through the ATP-binding cassette transporters analyzed. Indeed, we found nilotinib to be an inhibitor of hOCT1, MDR1 and ABCG2. The efflux transporters MDR1, MRP1 and ABCG2 are expressed on CML CD34(+) cells at 13.5, 108 and 291% of control, respectively, although hOCT1 expression was absent; however, inhibition of efflux transporter activity did not potentiate the effect of nilotinib on apoptosis, Bcr-Abl inhibition or CML CD34(+) cell proliferation. Therefore, we have found no evidence for either active uptake of nilotinib through hOCT1 or efflux through MDR1, MRP1 or ABCG2, and it is therefore unlikely that these transporters will have any effect on the clinical response to this drug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Antigens, CD34 / metabolism
  • Antineoplastic Agents / pharmacokinetics*
  • Apoptosis / drug effects*
  • Benzamides
  • Biological Transport, Active / drug effects
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Dogs
  • Humans
  • Imatinib Mesylate
  • Kidney / cytology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / pathology
  • Lipid Bilayers / metabolism
  • Multidrug Resistance-Associated Proteins / metabolism
  • Neoplasm Proteins / metabolism
  • Organic Cation Transporter 1 / metabolism
  • Piperazines / pharmacokinetics
  • Pyrimidines / pharmacokinetics*

Substances

  • 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
  • ABCB1 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antigens, CD34
  • Antineoplastic Agents
  • Benzamides
  • Carrier Proteins
  • Lipid Bilayers
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • Organic Cation Transporter 1
  • Piperazines
  • Pyrimidines
  • Imatinib Mesylate
  • multidrug resistance-associated protein 1