Lack of interactions between breast cancer resistance protein (BCRP/ABCG2) and selected antiepileptic agents

被引:57
作者
Cerveny, L
Pavek, P
Malakova, J
Staud, F
Fendrich, Z
机构
[1] Charles Univ Prague, Fac Pharm Hradec Kralove, Dept Pharmacol & Toxicol, Hradec Kralove 50005, Czech Republic
[2] Charles Univ Hosp, Dept Clin Biochem & Diagnost, Hradec Kralove, Czech Republic
关键词
breast cancer resistance protein; BCRP; ABCG2; antiepileptic drugs; transport; refractory epilepsy; transporter;
D O I
10.1111/j.1528-1167.2006.00453.x
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Purpose: Recent studies have indicated constitutive expression of efflux transporter, breast cancer resistance protein (BCRP, ABCG2), in endothelial cells of the blood-brain barrier (BBB). In epileptogenic brain tumors such as ganglioma, astrocytoma, anaplastic astrocytomas, or glioma multiforme, strong expression of BCRP in the microvasculature of the BBB was observed. Therefore it was hypothesized that this phenomenon could critically influence the bioavailability of drugs in these tumors and potentially contribute to the failure of antiepileptic treatment. The aim of this study was to test whether some commonly used antiepileptic drugs (AEDs) are substrates transported by human BCRP. In particular, we focused on phenobarbital, phenytoin, ethosuximide, primidone, valproate, carbamazepine, clonazepam, and lamotrigine. Furthermore, the inhibitory potency of these AEDs to BCRP was examined. Methods: To study substrate affinity of tested AEDs to BCRP, transport experiments were performed in epithelial BCRP-expressing MDCKII-BCRP and MDCKII-parent cell lines cultured on microporous membrane. For detection of inhibitory potency of AEDs to BCRP, accumulation assays were carried out in MEF3.8-BCRP cells with known BCRP substrates, BODIPY FL prazosin and mitoxantrone. Results: No obvious interactions of tested AEDs with BCRP transporter were observed. Therefore these drugs in relevant therapeutic concentrations are neither substrates nor inhibitors of BCRP. Conclusions: Based on our in vitro data we can conclude that resistance to treatment with the tested AEDs probably is not caused by the overexpression of BCRP in the BBB of epileptogenic brain tumors.
引用
收藏
页码:461 / 468
页数:8
相关论文
共 34 条
[1]  
Allen JD, 2002, MOL CANCER THER, V1, P417
[2]  
Allikmets R, 1998, CANCER RES, V58, P5337
[3]   Localization of breast cancer resistance protein (BCRP) in microvessel endothelium of human control and epileptic brain [J].
Aronica, E ;
Gorter, JA ;
Redeker, S ;
van Vliet, EA ;
Ramkema, M ;
Scheffer, GL ;
Scheper, RJ ;
van der Valk, P ;
Leenstra, S ;
Baayen, JC ;
Spliet, WGM ;
Troost, D .
EPILEPSIA, 2005, 46 (06) :849-857
[4]   Expression and cellular distribution of multidrug resistance-related proteins in the hippocampus of patients with mesial temporal lobe epilepsy [J].
Aronica, E ;
Gorter, JA ;
Ramkema, M ;
Redeker, S ;
Özbas-Gerçeker, F ;
van Vliet, EA ;
Scheffer, GL ;
Scheper, RJ ;
van der Valk, P ;
Baayen, JC ;
Troost, D .
EPILEPSIA, 2004, 45 (05) :441-451
[5]   Localisation of breast cancer resistance protein in microvessel endothelium of human brain [J].
Cooray, HC ;
Blackmore, CG ;
Maskell, L ;
Barrand, MA .
NEUROREPORT, 2002, 13 (16) :2059-2063
[6]   MULTIDRUG-RESISTANCE GENE (P-GLYCOPROTEIN) IS EXPRESSED BY ENDOTHELIAL-CELLS AT BLOOD-BRAIN BARRIER SITES [J].
CORDONCARDO, C ;
OBRIEN, JP ;
CASALS, D ;
RITTMANGRAUER, L ;
BIEDLER, JL ;
MELAMED, MR ;
BERTINO, JR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (02) :695-698
[7]   Reversal of resistance by GF120918 in cell lines expressing the ABC half-transporter, MXR [J].
de Bruin, M ;
Miyake, K ;
Litman, T ;
Robey, R ;
Bates, SE .
CANCER LETTERS, 1999, 146 (02) :117-126
[8]   Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy [J].
Dombrowski, SM ;
Desai, SY ;
Marroni, M ;
Cucullo, L ;
Goodrich, K ;
Bingaman, W ;
Mayberg, MR ;
Bengez, L ;
Janigro, D .
EPILEPSIA, 2001, 42 (12) :1501-1506
[9]   New antiepileptic drugs: Review on drug interactions [J].
Hachad, H ;
Ragueneau-Majlessi, I ;
Levy, RH .
THERAPEUTIC DRUG MONITORING, 2002, 24 (01) :91-103
[10]   Expression of multidrug resistance-associated protein (MRP) in brain microvessel endothelial cells [J].
Han, HY ;
Secrest, DT ;
Mark, KS ;
Carney, D ;
Brandquist, C ;
Elmquist, WF ;
Miller, DW .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1998, 243 (03) :816-820