Interaction between the efflux transporter BCRP ( ABCG2) and the anti-HIV drug Efavirenz in rats

PERONI RN.,DI GENNARO SS., HOCT C., CHIAPPETTA DA., SOSNIK A., RUBIO MC., BRAMUGLIA G.

Buenos Aires,-Argentina

Simposio; International Symposium on drug transport and metabolism; 2009

IUPHAR- SAFE

Interaction between the efflux transporter BCRP (ABCG2) and the anti-HIV drug EFAVIRENZ in rats Peroni RN1,2, Di Gennaro SS1, Hocht C2, Chiappetta DA3, Sosnik A3, Rubio MC1,2, Bramuglia GF2 1Instituto de Investigaciones Farmacológicas (CONICET-UBA); 2Cátedra de Farmacología (FFyB-UBA); 3Cátedra de Farmacotecnia (FFyB-UBA), Buenos Aires, Argentina   OBJECTIVES: Breast cancer resistant protein (BCRP/ABCG2) is a member of the superfamily of ABC transporters that affects drug disposition (1). The substantial expression of BCRP in organs important for drug disposition, such as small intestine (2) and blood-brain barrier (3), implies that BCRP could affect the absorption and distribution of drugs that are BCRP substrates. The non-nucleoside reverse transcriptase inhibitor efavirenz (EFV) is an anti-HIV drug, used in combination therapy, which significantly inhibits BCRP in vitro (4). This study was conducted to investigate the role of BCRP in the intestinal absorption and in the delivery to the central nervous system (CNS) of EFV and the influence of the chronic treatment with EFV 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 using ileum everted sacs and by CNS microdialysis techniques, respectively. BCRP expression was assessed by Western Blot after oral administration by gavage of 25 mg/kg EFV or its vehicle (Pluronic F127 10%, pH 5.0), daily during five days (5). RESULTS: In control rats, the concentration-dependent efflux of EFV (1-10 mM) observed in ileum everted sacs was almost completely blocked by pretreatment with the specific BCRP inhibitor fumitremorgin C (10 µM). Moreover, the delivery of EFV to CNS after a single i.v. administration of 20 mg/kg was increased two-fold after treatment with the BCRP inhibitor gefitinib (20 mg/kg, i.p.). Furthermore, an increase in the expression of BCRP in the small intestine and in the blood brain barrier was observed in both tissues after a 5-day treatment with EFV. CONCLUSIONS: Our study demonstrates that the intestinal absorption and the distribution into the CNS of EFV was modulated by BCRP in rats, and that EFV itself could modulate BCRP expression which in turn could influence the bioavailability and delivery of this drug to target or sanctuary HIV-sites. 1 Rocchi E, Khodjakov A, Volk EL, Yang CH, Litman T, Bates SE, Schneider E. Biochem Biophys Res Commun. 271: 42-46 (2000). 2 MacLean C, Moenning U, Reichel A, Fricker G. Drug Metab Dispos. 36: 1249-1254 (2008). 3 Cooray HC, Blackmore CG, Maskell L, and Barrand MA. Neuroreport13: 2059–2063 (2002). 4 Weiss J, Rose J, Storch CH, Ketabi-Kiyanvash N, Sauer A, Haefeli WE, Efferth T. J Antimicrob Chemother 59: 238-245 (2007). 5 Goffinet C, Allespach I, Keppler OT. Proc Natl Acad Sci U S A 104: 1015-1020 (2007).