[Show abstract][Hide abstract] ABSTRACT: Imatinib, a protein tyrosine kinase inhibitor, may prevent the growth of glioblastoma cells. Unfortunately, its brain distribution is restricted by p-glycoprotein (p-gp or multidrug resistance protein Mdr1a), and probably by breast cancer resistance protein (Bcrp1), two efflux pumps expressed at the blood-brain barrier (BBB). We have used in situ brain perfusion to investigate the mechanisms of imatinib transport across the mouse BBB. The brain uptake of imatinib in wild-type mice was limited by saturable efflux processes. The inhibition of p-gp, by valspodar and zosuquidar, increased imatinib uptake (2.5-fold), as did the deficiency of p-gp in Mdr1a/1b(-/-) mice (5.5-fold). Perfusing imatinib with the p-gp/Bcrp1 inhibitor, elacridar, enhanced the brain uptake of imatinib in wild-type (4.1-fold) and Mdr1a/1b(-/-) mice (1.2-fold). However, the brain uptake of imatinib was similar in wild-type and Bcrp1(-/-) mice when it was perfused at a non-saturating concentration. The brain uptake of CGP74588, an active metabolite of imatinib, was low. It was increased by perfusion with elacridar (twofold), but not with valspodar and zosuquidar. CGP74588 uptake was 1.5 times greater in Bcrp1(-/-) mice than in wild-type mice. These data suggest that imatinib transport at the mouse BBB is limited by p-gp and probably by Bcrp1, and that CGP74588 transport is restricted by Bcrp1.
Full-text · Article · Oct 2007 · Journal of Neurochemistry
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
Full-text · Article · Oct 2007 · Pharmaceutical Research
[Show abstract][Hide abstract] ABSTRACT: The combination of imatinib mesylate and hydroxyurea provides a therapeutic benefit in patients with glioblastoma, although each drug is not effective when used alone. The increase of brain delivery of one or both drugs has been suggested to be a potential cause of this therapeutic benefit. The cross-influence of hydroxyurea and imatinib on their respective brain distribution was examined in mice and rats. We used in situ brain perfusion in mice to determine whether these two drugs have an influence on their respective initial transport across the blood-brain barrier. The brain penetration of hydroxyurea, assessed by its brain uptake clearance, Knet, was low in mice (approximately 0.10 microl/g/s) and not modified by coperfusion of imatinib (0.5-500 microM). Likewise, the brain penetration of imatinib was low (Knet, 1.39 +/- 0.17 microl/g/s) and not modified by direct coperfusion of hydroxyurea (0.2-1000 microM) or by intravenous pretreatment with 15 or 1000 mg/kg hydroxyurea. We also examined a potential time-dependent influence of hydroxyurea on imatinib brain distribution after sustained subcutaneous administration in rats using an implantable osmotic pump. The brain penetration of imatinib in rats increased with time, approximately 1.6-fold (p < 0.01) after 7 and 14 days' infusion of imatinib (3 mg/day) with or without hydroxyurea (15 mg/day), and was not influenced by hydroxyurea. The results of these two sets of experiments indicate that hydroxyurea has no significant influence on the brain distribution of imatinib in mice and rats.
Full-text · Article · Jan 2007 · Drug Metabolism and Disposition