ININFA   02677
INSTITUTO DE INVESTIGACIONES FARMACOLOGICAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
The anti-HIV drug EFAVIRENZ is substrate and modulates the expression of the efflux transporter BCRP (ABCG2) in rats
Autor/es:
PERONI RN; HOCHT C; CHIAPPETTA DA; DI GENNARO SS; RUBIO MC; SOSNIK A; BRAMUGLIA GF
Lugar:
Kottayam, India
Reunión:
Conferencia; First World Conference on Nanomedicine and Drug Delivery; 2010
Institución organizadora:
International Association of Nanotechnology
Resumen:
OBJECTIVES: Breast cancer resistant protein (BCRP/ABCG2) is an efflux pump included in the ATP-binding cassette superfamily (Rocchi E, et al, Biochem Biophys Res Commun 271:42-46, 2000). The substantial expression of BCRP in small intestine (MacLean et al, Drug Metab Dispos. 36:1249-1254, 2008), blood-brain barrier (BBB) (Cooray et al, Neuroreport, 13:2059–2063, 2002) and other tissues may affect the absorption and biodistribution of its substrates. For example, it was demonstrated that a high level of BCRP expression in CD4-T cells confers cellular resistance to nucleoside reverse transcriptase inhibitors (NRTIs), which are key drugs in the combined pharmacotherapy of the infection by the human immunodeficiency virus type-1 (HIV-1)  (Wang et al, Mol Pharmacol 63:65–72, 2003). The non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz is an antiretroviral drug that significantly inhibits BCRP in vitro (Weiss et al, J Antimicrob Chemother. 59:238-245, 2007). The goals of the present study were (i) to investigate the role of BCRP in both the intestinal absorption of EFV and its delivery to the central nervous system (CNS) and (ii) to evaluate the influence of the chronic EFV treatment on the expression of BCRP in adult male rats. METHODS: Adult male Sprague-Dawley rats were used to perform all the experiments. The intestinal permeation rate and the delivery to CNS of EFV were investigated by the ileum everted sac method and a microdialysis technique, respectively. BCRP expression after the oral administration of EFV (gavage, 20 mg/kg EFV solubilized in 10% Pluronic F127 polymeric micelles or drug-free 10% Pluronic F127, pH 5.0, once-a-day) during five days was assessed by Western Blot. RESULTS: In control rats, the concentration-dependent efflux of EFV (0.1-2.5 mM) observed in ileum everted sacs was almost completely blocked by the pre-treatment with the specific BCRP inhibitor fumitremorgin C (10 µM). Moreover, the delivery of EVF to the CNS after a single i.v. administration (20 mg/kg) was two-fold increased after treatment with the BCRP inhibitor gefitinib (20 mg/kg, i.p.). Furthermore, a significant increase in the expression of BCRP in the small intestine and the BBB was found after a 5-days treatment with EFV. CONCLUSIONS: Our study demonstrates that EFV is a substrate of BCRP in rats and that the drug itself modulates the expression of the efflux pump, which in turn could influence the bioavailability and delivery of the drug into HIV sanctuaries such as the CNS.   Acknowledgements: This study was supported by the University of Buenos Aires (UBA, Grants UBACYT 08/B067 and UBACyT-B424) and by the Agencia para la Promoción Científica y Técnica (ANPCyT, Grant BID PICT 01524). Contact: Dr. Roxana Peroni, roxanaperoni@yahoo.com.ar