Ryoko Yumoto1, Teruo Murakami, Mikihisa Takano. 1. 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.
Abstract
PURPOSE: The expression and function of P-glycoprotein (P-gp) in the intestine in carbon tetrachloride-induced acute hepatic failure (AHF) were evaluated in rats. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
PURPOSE: The expression and function of P-glycoprotein (P-gp) in the intestine in carbon tetrachloride-induced acute hepatic failure (AHF) were evaluated in rats. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: K S Lown; R R Mayo; A B Leichtman; H L Hsiao; D K Turgeon; P Schmiedlin-Ren; M B Brown; W Guo; S J Rossi; L Z Benet; P B Watkins Journal: Clin Pharmacol Ther Date: 1997-09 Impact factor: 6.875
Authors: Matthew P Kosloski; Haoyu Wang; David Pugatch; Federico J Mensa; Edward Gane; Eric Lawitz; Thomas C Marbury; Richard A Preston; Jens Kort; Wei Liu Journal: Eur J Clin Pharmacol Date: 2018-10-19 Impact factor: 2.953