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Modulated function of tissue efflux transporters under hyperbilirubinemia in rats.
Eur J Pharmacol. 2010 Jun 25; 636(1-3):166-72.EJ

Abstract

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.

Authors+Show Affiliations

Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

20362568

Citation

Yokooji, Tomoharu, et al. "Modulated Function of Tissue Efflux Transporters Under Hyperbilirubinemia in Rats." European Journal of Pharmacology, vol. 636, no. 1-3, 2010, pp. 166-72.
Yokooji T, Mori N, Murakami T. Modulated function of tissue efflux transporters under hyperbilirubinemia in rats. Eur J Pharmacol. 2010;636(1-3):166-72.
Yokooji, T., Mori, N., & Murakami, T. (2010). Modulated function of tissue efflux transporters under hyperbilirubinemia in rats. European Journal of Pharmacology, 636(1-3), 166-72. https://doi.org/10.1016/j.ejphar.2010.03.042
Yokooji T, Mori N, Murakami T. Modulated Function of Tissue Efflux Transporters Under Hyperbilirubinemia in Rats. Eur J Pharmacol. 2010 Jun 25;636(1-3):166-72. PubMed PMID: 20362568.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modulated function of tissue efflux transporters under hyperbilirubinemia in rats. AU - Yokooji,Tomoharu, AU - Mori,Nobuhiro, AU - Murakami,Teruo, Y1 - 2010/04/01/ PY - 2010/01/19/received PY - 2010/02/24/revised PY - 2010/03/12/accepted PY - 2010/4/6/entrez PY - 2010/4/7/pubmed PY - 2010/8/10/medline SP - 166 EP - 72 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 636 IS - 1-3 N2 - 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. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/20362568/Modulated_function_of_tissue_efflux_transporters_under_hyperbilirubinemia_in_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(10)00239-6 DB - PRIME DP - Unbound Medicine ER -