Interaction of imatinib with human organic ion carriers.
Article Details
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Hu S, Franke RM, Filipski KK, Hu C, Orwick SJ, de Bruijn EA, Burger H, Baker SD, Sparreboom A
Interaction of imatinib with human organic ion carriers.
Clin Cancer Res. 2008 May 15;14(10):3141-8. doi: 10.1158/1078-0432.CCR-07-4913.
- PubMed ID
- 18483382 [ View in PubMed]
- Abstract
PURPOSE: The activity of imatinib in leukemia has recently been linked with expression of the organic cation transporter 1 (OCT1) gene SLC22A1. Here, we characterized the contribution of solute carriers to imatinib transport in an effort to further understand mechanisms involved in the intracellular uptake and retention (IUR) of the drug. EXPERIMENTAL DESIGN: IUR of [3H]imatinib was studied in Xenopus laevis oocytes and HEK293 cells expressing OATP1A2, OATP1B1, OATP1B3, OCT1-3, OCTN1-2, or OAT1-3. Gene expression was determined in nine leukemia cell lines using the Affymetrix U133 array. RESULTS: Imatinib was not found to be a substrate for OCT1 in oocytes (P = 0.21), whereas in HEK293 cells IUR was increased by only 1.20-fold relative to control cells (P = 0.002). Furthermore, in 74 cancer patients, the oral clearance of imatinib was not significantly altered in individuals carrying reduced-function variants in SLC22A1 (P = 0.99). Microarray analysis indicated that SLC22A1 was interrelated with gene expression of various transporters, including ABCB1, ABCC4, ABCG2 (negative), and OATP1A2 (positive). Imatinib was confirmed to be a substrate for the three efflux transporters (P < 0.05) as well as for OATP1A2 (P = 0.0001). CONCLUSIONS: This study suggests that SLC22A1 expression is a composite surrogate for expression of various transporters relevant to imatinib IUR. This observation provides a mechanistic explanation for previous studies that have linked SLC22A1 with the antitumor activity of imatinib. Because of its high expression in the intestine, ciliary body, gliomas, and leukemia cells, OATP1A2 may play a key role in imatinib pharmacokinetics-pharmacodynamics.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Imatinib Multidrug resistance-associated protein 4 Protein Humans NoSubstrateDetails Imatinib Solute carrier family 22 member 5 Protein Humans NoSubstrateDetails Imatinib Solute carrier organic anion transporter family member 1A2 Protein Humans NoSubstrateDetails Imatinib Solute carrier organic anion transporter family member 1B3 Protein Humans NoSubstrateDetails