title: Interaction of imatinib with human organic ion carriers.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphia, TN 38105, USA.
authors.forename: Shuiying
authors.initials: S
authors.lastname: Hu
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Franke
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Filipski
authors.forename: Chaoxin
authors.initials: C
authors.lastname: Hu
authors.forename: Shelley J
authors.initials: SJ
authors.lastname: Orwick
authors.forename: Ernst A
authors.initials: EA
authors.lastname: de Bruijn
authors.forename: Herman
authors.initials: H
authors.lastname: Burger
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D001549:Benzamides; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D000068877:Imatinib Mesylate; D027702:Organic Cation Transporter 1 / Q000235:genetics* / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011743:Pyrimidines / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D027702:Organic Cation Transporter 1; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate