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

被引:61
作者
Bihorel, Sebastien
Camenisch, Gian
Lemaire, Michel
Scherrmann, Jean-Michel
机构
[1] Univ Paris 07, INSERM, CNRS, U 705, Paris, France
[2] Univ Paris 05, Fac Pharm, Pharmacokinet Lab, Paris, France
[3] Nova Pharma AG, Dept Drug Metab & Pharmacokinet, Basel, Switzerland
关键词
brain; breast cancer resistance protein 1; imatinib; metabolites; P-glycoprotein;
D O I
10.1007/s11095-007-9278-4
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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 (similar to 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.
引用
收藏
页码:1720 / 1728
页数:9
相关论文
共 39 条
[1]   Delivery of therapeutic agents to the central nervous system: the problems and the possibilities [J].
Begley, DJ .
PHARMACOLOGY & THERAPEUTICS, 2004, 104 (01) :29-45
[2]   How to measure drug transport across the blood-brain barrier [J].
Bickel U. .
NeuroRX, 2005, 2 (1) :15-26
[3]   The effect of Bcrp1 (Abcg2) on the in vivo pharmacokinetics and brain penetration of imatinib mesylate (gleevec): Implications for the use of breast cancer resistance protein and P-glycoprotein inhibitors to enable the brain penetration of imatinib in patients [J].
Breedveld, P ;
Pluim, D ;
Cipriani, G ;
Wielinga, P ;
van Tellingen, O ;
Schinkel, AH ;
Schellens, JHM .
CANCER RESEARCH, 2005, 65 (07) :2577-2582
[4]   Pharmacology of imatinib (STI571) [J].
Buchdunger, E ;
O'Reilly, T ;
Wood, J .
EUROPEAN JOURNAL OF CANCER, 2002, 38 :S28-S36
[5]   Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump [J].
Burger, H ;
van Tol, H ;
Boersma, AWM ;
Brok, M ;
Wiemer, EAC ;
Stoler, G ;
Nooter, K .
BLOOD, 2004, 104 (09) :2940-2942
[6]  
Choo EF, 2000, DRUG METAB DISPOS, V28, P655
[7]   Nonlinear accumulation in the brain of the new taxoid TXD258 following saturation of P-glycoprotein at the blood-brain barrier in mice and rats [J].
Cisternino, S ;
Bourasset, F ;
Archimbaud, Y ;
Sémiond, D ;
Sanderink, G ;
Scherrmann, JM .
BRITISH JOURNAL OF PHARMACOLOGY, 2003, 138 (07) :1367-1375
[8]  
Cohen MH, 2005, CLIN CANCER RES, V11, P12
[9]   Development of an in situ mouse brain perfusion model and its application to mdr1a P-glycoprotein-deficient mice [J].
Dagenais, C ;
Rousselle, C ;
Pollack, GM ;
Scherrmann, JM .
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 2000, 20 (02) :381-386
[10]  
Dagher R, 2002, CLIN CANCER RES, V8, P3034