Differential effect of acute hepatic failure on in vivo and in vitro P-glycoprotein functions in the intestine.
OBJECTIVE
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.
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.
Ryoko
R
Yumoto
Teruo
T
Murakami
Mikihisa
M
Takano
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism*; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002251:Carbon Tetrachloride