Cerveny Lukas, Pavek Petr, Malakova Jana, Staud Frantisek, Fendrich Zdenek
Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague.
Epilepsia. 2006 Mar;47(3):461-8. doi: 10.1111/j.1528-1167.2006.00453.x.
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.
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.
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.
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.
近期研究表明，血脑屏障（BBB）内皮细胞中存在外排转运蛋白乳腺癌耐药蛋白（BCRP，ABCG2）的组成型表达。在神经节瘤、星形细胞瘤、间变性星形细胞瘤或多形性胶质母细胞瘤等致痫性脑肿瘤中，观察到BBB微血管中BCRP的强表达。因此，推测这种现象可能会严重影响这些肿瘤中药物的生物利用度，并可能导致抗癫痫治疗失败。本研究的目的是测试一些常用的抗癫痫药物（AEDs）是否是人类BCRP转运的底物。特别是，我们重点研究了苯巴比妥、苯妥英、乙琥胺、扑米酮、丙戊酸盐、卡马西平、氯硝西泮和拉莫三嗪。此外，还检测了这些AEDs对BCRP的抑制效力。
为研究受试AEDs对BCRP的底物亲和力，在微孔膜上培养的表达上皮BCRP的MDCKII-BCRP和MDCKII亲本细胞系中进行转运实验。为检测AEDs对BCRP的抑制效力，在具有已知BCRP底物BODIPY FL哌唑嗪和米托蒽醌的MEF3.8-BCRP细胞中进行蓄积实验。
未观察到受试AEDs与BCRP转运蛋白有明显相互作用。因此，这些药物在相关治疗浓度下既不是BCRP的底物也不是抑制剂。
基于我们的体外数据，我们可以得出结论，受试AEDs治疗耐药可能不是由致痫性脑肿瘤BBB中BCRP的过表达引起的。
