Yumoto Ryoko, Murakami Teruo, Takano Mikihisa
Department of Pharmaceutics and Therapeutics, Programs for Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
Pharm Res. 2003 May;20(5):765-71. doi: 10.1023/a:1023485519485.
The expression and function of P-glycoprotein (P-gp) in the intestine in carbon tetrachloride-induced acute hepatic failure (AHF) were evaluated in rats.
The expression of P-gp, in vivo absorption and exsorption of P-gp substrates (digoxin and rhodamine 123), and in vitro efflux transport of these P-gp substrates were studied in the absence and presence of a P-gp inhibitor (verapamil or cyclosporin A) using the distal region of small intestine of control and AHF rats.
Western blot analysis revealed that intestinal P-gp expression level remained unchanged, or rather increased, in AHF. The in vivo intestinal P-gp function was significantly lower in AHF, as evaluated by the absorption and exsorption of P-gp substrates. In contrast, in vitro P-gp function was significantly higher in AHF, as evaluated by the efflux transport of P-gp substrates across the everted intestine. Collectively, the intestinal P-gp function was differently affected by AHF between in vivo and in vitro conditions.
The in vivo intestinal P-gp function was suppressed in AHF, which could not be predicted from in vitro functional studies nor from P-gp expression level. The discrepancy between in vivo and in vitro results may be explained by the presence of endogenous P-gp inhibitors in the plasma of AHF rats.
