title: Lack of ABC transporter autoinduction in mice following long-term exposure to imatinib.
abstract: OBJECTIVE
  Chronic imatinib exposure has been shown to result in upregulation of the ABCB1 (P-glycoprotein) and ABCG2 (BCRP) transporters in vitro, for which imatinib is a substrate. This finding, along a trend towards increasing imatinib clearance over time in patients, has resulted in the suggestion that pharmacokinetic resistance may be contributing to eventual treatment failure. Here, we sought to determine the effects of long-term imatinib exposure on apparent oral clearance and transporter expression in vivo.
  
  
  RESULTS
  Plasma and liver concentrations of imatinib did not change significantly (P > 0.1) over the course of treatment, suggesting that steady-state had been reached. There was no increase in Abcb1 or Abcg2 expression in liver samples, whereas expression of these transporters in intestinal samples was highly variable, and no increase was apparent.
  
  
  METHODS
  Male BALB/c mice were treated daily-times 5 with oral imatinib at a dose of 50 mg/kg for 4 consecutive weeks. Imatinib concentrations were measured in plasma and liver tissue prior to treatment and following each week of dosing. Western blotting of liver and intestinal tissue lysates was performed to assess expression of Abcb1 and Abcg2.
  
  
  CONCLUSIONS
  Imatinib does not appear to cause upregulation of ABC transporters in the hepatic and intestinal compartments in mice. These data do not support the possibility that autoinduction contributes to the development of resistance to imatinib.
authors: Clinical Pharmacology Program, SAIC-Frederick, Inc., Frederick, Maryland, USA.
authors: Erin R
authors: ER
authors: Gardner
authors: Alex
authors: A
authors: Sparreboom
authors: Jaap
authors: J
authors: Verweij
authors: William D
authors: WD
authors: Figg
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000187:drug effects; D000199:Actins / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D004305:Dose-Response Relationship, Drug; D000068877:Imatinib Mesylate; D007700:Kinetics; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D018528:ATP-Binding Cassette Transporters; D000199:Actins; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate