Imatinib Uptake into Cells is Not Mediated by Organic Cation Transporters OCT1, OCT2, or OCT3, But is Influenced by Extracellular pH.

Details

Serval ID
serval:BIB_6F47958A0A5D
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Imatinib Uptake into Cells is Not Mediated by Organic Cation Transporters OCT1, OCT2, or OCT3, But is Influenced by Extracellular pH.
Journal
Drug metabolism letters
Author(s)
Blanc Mettral J., Faller N., Cruchon S., Sottas L., Buclin T., Schild L., Choong E., Nahimana A., Decosterd L.A.
ISSN
1874-0758 (Electronic)
ISSN-L
1872-3128
Publication state
Published
Issued date
2019
Peer-reviewed
Oui
Volume
13
Number
2
Pages
102-110
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Cancer cells undergo genetic and environmental changes that can alter cellular disposition of drugs, notably by alterations of transmembrane drug transporters expression. Whether the influx organic cation transporter 1 (OCT1) encoded by the gene SLC221A1 is implicated in the cellular uptake of imatinib is still controversial. Besides, imatinib ionization state may be modulated by the hypoxic acidic surrounding extracellular microenvironment.
To determine the functional contribution of OCTs and extracellular pH on imatinib cellular disposition.
We measured imatinib uptake in two different models of selective OCTs drug transporter expression (transfected Xenopus laevis oocytes and OCT-expressing HEK293 human cells), incubated at pH 7.4 and 6, using specific mass spectrometry analysis.
Imatinib cellular uptake occurred independently of OCT1- OCT2- or OCT3-mediated drug transport at pH 7.4. Uptake of the OCTs substrate tetraethylammonium in oocytes remained intact at pH 6, while the accumulation of imatinib in oocytes was 10-fold lower than at pH 7.4, irrespectively of OCTs expressions. In OCT1- and OCT2-HEK cells at pH 6, imatinib accumulation was reduced by 2- 3-fold regardless of OCTs expressions. Since 99.5% of imatinib at pH6 is under the cationic form, the reduced cellular accumulation of imatinib at such pH may be explained by the lower amount of uncharged imatinib remaining for passive diffusion across cellular membrane.
Imatinib is not a substrate of OCTs 1-3 while the environmental pH modulates cellular disposition of imatinib. The observation that a slightly acidic extracellular pH influences imatinib cellular accumulation is important, considering the low extracellular pH reported in the hematopoietic leukemia/ cancer cell microenvironment.
Keywords
Animals, Extracellular Space/chemistry, HEK293 Cells, Humans, Hydrogen-Ion Concentration, Imatinib Mesylate/pharmacokinetics, Imatinib Mesylate/therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology, Octamer Transcription Factor-1/metabolism, Oocytes, Organic Cation Transport Proteins/metabolism, Organic Cation Transporter 2/metabolism, Protein Kinase Inhibitors/pharmacokinetics, Protein Kinase Inhibitors/therapeutic use, Xenopus laevis, Imatinib, MATE1, OCT1, OCT2, OCT3, acidic extracellular pH, cellular concentrations, chronic myeloid leukemia, influx organic cation transporters, mass spectrometry, multidrug and toxin extrusion protein 1.
Pubmed
Create date
25/03/2019 10:28
Last modification date
17/09/2020 8:14
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