An experimental model of metabolic syndrome produced modification of P-gp expression in the intestine and in Blood Brain Barrier

FILIA MF.,NOVAK A., GODOY Y., RUBIO MC., GHANEM CI., CELUCH SM.

Rosario-Argentina

Congreso; XLI Reunion anual de la Asociación Argentina de Farmacología Experimental; 2009

SAFE

011-12 AN EXPERIMENTAL MODEL OF METABOLIC SYN0ROME produced MODIFICATION OF P-gp EXPRESSION in the intestine and IN Blood Brain Barrier. 1 Tilia, M.F., "Novak, A., ´Godoy, Y., ´Rubio M.C., "Ghanem C.I., ´Celuch, S.M. ´ININFA (CONICET-UBA); C4t. JFisiopatologia y 3Farmacotecnia II (FFyB, UBA). Junta 956,5° P. Buenos Aires, cghanero@ffyb.uba.ar Several studies demonstrated alterations in P-gp expression or activity in type 1 diabetes. The metabolic syndrome (MS) is a combination of risk factors leading to type 2 diabetes and cardiovascular disease. The aim of this study was to investigate P-gp expression and activity in an experimental model of MS. Male Sprague-Dawley rats received standard solid diet and either tap water (C) or drinking water containing 15% fructose (FRU) during two months. The animals were lasted for 12 h before the experiments. The P-gp expression was estimated by western-blot in intestine brush border and in blood-brain barrier capillaries (BBB). The activity of P-gp was measured in everted intestinal sacs using rhodamine 123 (Rho, 15 uM) as substrate. The expression of intestinal P-gp decreased in FRU vs C (FRU=44±15 %; CMOO±13%; p<0.05; n=3). The expression of P-gp in BBB was also decreased in FRU rate (FRU=49±17 %; O100±19%; p<0.05). The intestinal activity of P-gp was decreased to 50 % of the control group value (p<0.05; n=5). The Rho excretion was lineal up to 40 min and the slope was 0.0284*0.0040 in FRU group compared to 0.0552±0.0089 in C, expressed as nmol Rhc/miiVg tissue (p<0.05; n=5). P-gp activity was confirmed in the presence of verapamil (100 uM), a known P-gp inhibitor, which abolished the differences between groups. It is concluded that MS decreased intestinal P-gp expression and activity in rats. This effect did not appear to be tissue-specific. These changes could modify the pharmacofcinetics of drugs that are substrates of the P-gp. StgportedfyPIP 112-200801-00330 CONJCET, B609- UBA and PICT2007-1039, ANPCyT.