Background: 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.
Objectives: To determine the functional contribution of OCTs on imatinib cellular disposition.
Methods: 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.
Results: 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.
Conclusions: 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.