Lack of Interactions between Breast Cancer Resistance Protein (BCRP/ABCG2) and Selected Antiepileptic Agents

Abstract

Summary: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 BCRPexpressing 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.

Polymorphisms of ABCG2, ABCB1 and HNF4α are associated with Lamotrigine trough concentrations in epilepsy patients

“…An in vitro study showed a lack of association between ABCG2 and LTG by using human ABCG2-expressing MadineDarby canine kidney cells [25], while another in vivo study [26] using the ABCG2 knockout mice showed that ABCG2 may be involved in the restriction of LTG distribution in the brain, which was confirmed by a recent study [10]. In the present study, ABCG2 rs2231142 and rs3114020 were found to significantly influence LTG concentration.…”

Valproic Acid Is Not a Substrate for P-glycoprotein or Multidrug Resistance Proteins 1 and 2 in a Number of in Vitro and in Vivo Transport Assays

“…An interesting candidate transporter in this respect may be the ABC transporter breast cancer resistance protein (ABCG2), which, like Pgp and MRP2, is expressed at the apical membrane of brain capillary endothelial cells, is involved in brain uptake of certain drugs and is up-regulated by seizures (van Vliet et al, 2005;Breedveld et al, 2006). However, in a recent study using MDCKII cells transfected with breast cancer resistance protein, no directional transport of VPA was observed (Cerveny et al, 2006).…”

Efficacy and Safety of Antiepileptic Drugs During Pregnancy: Pharmacogenetic Aspects

“…Воздействие ПЭП на плод связано с функ-ционированием транспортеров ЛС в плаценте, включая Р-гликопротеин aBcB1, протеин, ассо-циированный с множественной лекарственной устойчивостью Mrp1, и протеин резистентности рака груди Bcrp [15]. Необходимо учитывать, что ПЭП могут быть субстратами транспортеров ЛС (например, Р-гликопротеина).…”