title: Drug transporters and imatinib treatment: implications for clinical practice.
abstract: Imatinib mesylate is approved for the treatment of chronic myeloid leukemia (CML) and advanced gastrointestinal stromal tumors (GIST). Unfortunately, in the course of treatment, disease progression occurs in the majority of patients with GIST. Lowered plasma trough levels of imatinib over time potentially cause disease progression, a phenomenon known as "acquired pharmacokinetic drug resistance." This outcome may be the result of an altered expression pattern or activity of drug transporters. To date, the role of both efflux transporters (ATP-binding cassette transporters, such as ABCB1 and ABCG2) and uptake transporters [solute carriers such as organic cation transporter 1 (OCT1) and organic anion transporting polypeptide 1A2 (OATP1A2)] in imatinib pharmacokinetics and pharmacodynamics has been studied. In vitro experiments show a significant role of ABCB1 and ABCG2 in cellular uptake and retention of imatinib, although pharmacokinetic and pharmacogenetic data are still scarce and contradictory. ABCB1 and ABCC1 expression was shown in GIST, whereas ABCB1, ABCG2, and OCT1 were found in mononuclear cells in CML patients. Several studies have reported a clinical relevance of tumor expression or activity of OCT1 in CML patients. Further (clinical) studies are required to quantify drug transporter expression over time in organs involved in imatinib metabolism, as well as in tumor tissue. In addition, more pharmacogenetic studies will be needed to validate associations.
authors.affiliation: Department of Medical Oncology, Daniel den Hoed Cancer Center, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Karel
authors.initials: K
authors.lastname: Eechoute
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
authors.forename: Herman
authors.initials: H
authors.lastname: Burger
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Franke
authors.forename: Gaia
authors.initials: G
authors.lastname: Schiavon
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Loos
authors.forename: Erik A C
authors.initials: EA
authors.lastname: Wiemer
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
mesh_terms: D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D010879:Piperazines / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001549:Benzamides; D026901:Membrane Transport Proteins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate