Modulation of intestinal transport of 2,4-dinitrophenyl-S-glutathione, a multidrug resistance-associated protein 2 substrate, by bilirubin treatment in rats.
The effect of bilirubin treatment on intestinal transport of 2,4-dinitrophenyl-S-glutathione (DNP-SG), a substrate of multidrug resistance-associated protein 2 (MRP2), after application of 1-chloro-2, 4-dinitrobenzene (CDNB), a precursor of DNP-SG, was examined in rat intestine by the in-vitro everted sac, in-situ re-circulating perfusion, and in-situ loop methods. CDNB was taken up rapidly by jejunum and ileum, and the consequent intestinal efflux of DNP-SG, a glutathione conjugated metabolite of CDNB, was significantly higher in jejunum than in ileum in the in-situ and in-vitro studies. Co-administration of bilirubin (100 microM), as well as probenecid (1 mM) or ciclosporin (100 microM), with CDNB decreased the DNP-SG efflux in jejunum significantly, but not in ileum. The suppression of DNP-SG efflux in jejunum was also observed after intravenous administration of bilirubin (85.5 micromol kg-1), in which plasma bilirubin glucuronide levels were approximately 100 microM. In the in-vitro metabolism study, bilirubin exerted no significant effect on CDNB metabolism in the intestinal S9 fraction (supernatant of 9000 g). These results suggested that the diseased states accompanied with hyperbilirubinaemia might have increased the intestinal absorption, or oral bioavailability, of MRP2 substrates by suppressing MRP2 function at the proximal intestinal region.
Yokooji
Tomoharu
T
Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Murakami
Teruo
T
Ogawa
Kumiko
K
Yumoto
Ryoko
R
Nagai
Junya
J
Takano
Mikihisa
M
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001663:Bilirubin / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D004137:Dinitrochlorobenzene / Q000493:pharmacokinetics*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D007082:Ileum / Q000201:enzymology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000201:enzymology / Q000378:metabolism*; D007583:Jejunum / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity
D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D004137:Dinitrochlorobenzene; C030190:S-(2,4-dinitrophenyl)glutathione; D005982:Glutathione Transferase; D005978:Glutathione; D001663:Bilirubin