Modulated function of tissue efflux transporters under hyperbilirubinemia in rats.
The effect of hyperbilirubinemia on the function of tissue efflux transporters such as multidrug resistance-associated proteins (Mrps) and organic anion transporting polypeptides (Oatps) was examined by measuring tissue accumulation of 2,4-dinitrophenyl-S-glutathione (DNP-SG) after intravenous administration of 1-chloro-2,4-dinitrobenzene (CDNB), a precursor of DNP-SG, in rats. DNP-SG is known as a substrate of both Mrps and Oatps. Hyperbilirubinemia was induced by a bolus intravenous administration of bilirubin. Treatment with probenecid, an inhibitor for both Mrps and Oatps, significantly increased DNP-SG concentrations in the brain, heart, liver, kidney, jejunum, spleen and skeletal muscle as compared with those in control rats, suggesting the expression of some probenecid-sensitive efflux transporters in these tissues. Rats with more than 70 microM of unconjugated/conjugated bilirubin in plasma exhibited significantly higher DNP-SG concentrations in the brain, liver, jejunum, and skeletal muscle. These results suggested that probenecid-sensitive efflux transporters in tissues were suppressed functionally under hyperbilirubinemia. In conclusion, hyperbilirubinemia accompanied by obstructive jaundice is caused by various disease states, which may increase harmful toxicities of exogenously administered Mrps and/or Oatps substrate drugs at various tissues, by suppressing the efflux transporter's function systemically.
Yokooji
Tomoharu
T
Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
Mori
Nobuhiro
N
Murakami
Teruo
T
D000818:Animals; D001663:Bilirubin / Q000494:pharmacology; D004137:Dinitrochlorobenzene / Q000008:administration & dosage / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D006932:Hyperbilirubinemia / Q000097:blood / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D004137:Dinitrochlorobenzene; D026901:Membrane Transport Proteins; C030190:S-(2,4-dinitrophenyl)glutathione; D005978:Glutathione; D011339:Probenecid; D001663:Bilirubin