Modulation of the brain distribution of imatinib and its metabolites in mice by valspodar, zosuquidar and elacridar

Pharm Res. 2007 Sep;24(9):1720-8. doi: 10.1007/s11095-007-9278-4. Epub 2007 Mar 23.


Purpose: The selective protein tyrosine kinase inhibitor, imatinib, inhibits the growth of glioma cells in preclinical models, but its poor brain distribution limits its efficacy in patients. P-glycoprotein (P-gp, rodent Mdr1a/1b or Abcb1a/1b) and Breast cancer resistance protein (rodent Bcrp1 or Abcg2) were suggested to restrict the delivery of imatinib to the brain. This study evaluates the effect of administering selective inhibitors of these transporters together with imatinib on the systemic and cerebral disposition of imatinib in mice.

Materials and methods: Wild-type, Mdr1a/1b(-/-) and Bcrp1(-/-) mice were given imatinib intravenously, either alone, or with valspodar, zosuquidar (P-gp inhibitors), or elacridar (a P-gp and Bcrp1 inhibitor). The blood and brain concentrations of [(14)C]imatinib and its radioactive metabolites were determined.

Results: The blockade of P-gp by valspodar or zosuquidar (>3 mg/kg) enhanced the brain uptake of imatinib ( approximately 4-fold) in wild-type mice, but not that of its metabolites. Blockade of both P-gp and Bcrp1 by elacridar (>3 mg/kg) produced significantly greater brain penetration of imatinib (9.3-fold) and its metabolites (2.8-fold). In contrast, only the lack of P-gp enhanced imatinib brain penetration (6.4-fold) in knockout mice. These results of brain uptake correlated reasonably well with those obtained previously by our group using in situ brain perfusion.

Conclusions: Imatinib and its metabolites penetrate into the brain poorly and their penetration is limited by P-gp and (probably) Bcrp1. Administering imatinib together with P-gp (and Bcrp1) transporter inhibitors such as elacridar may improve the delivery of imatinib to the brain, making it potentially more effective against malignant gliomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / physiology
  • Acridines / pharmacology*
  • Animals
  • Antineoplastic Agents / pharmacokinetics*
  • Benzamides
  • Blood-Brain Barrier
  • Brain / metabolism*
  • Carbon Radioisotopes
  • Cyclosporins / pharmacology*
  • Dibenzocycloheptenes / pharmacology*
  • Imatinib Mesylate
  • Male
  • Mice
  • Piperazines / pharmacokinetics*
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Pyrimidines / pharmacokinetics*
  • Quinolines / pharmacology*
  • Tetrahydroisoquinolines / pharmacology*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Abcg2 protein, mouse
  • Acridines
  • Antineoplastic Agents
  • Benzamides
  • Carbon Radioisotopes
  • Cyclosporins
  • Dibenzocycloheptenes
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Quinolines
  • Tetrahydroisoquinolines
  • zosuquidar trihydrochloride
  • Imatinib Mesylate
  • Elacridar
  • valspodar