PMID: 8592681Nov 1, 1995Paper

Kinetic analysis of hepatobiliary transport for conjugated metabolites in the perfused liver of mutant rats (EHBR) with hereditary conjugated hyperbilirubinemia

Pharmaceutical Research
O TakenakaY Sugiyama

Abstract

Previously, we found that the biliary excretion of the 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040) glucuronide is severely impaired in Eisai hyperbilirubinemic rats (EHBR), while that of sulfate remains normal (Takenaka et al., J. Pharmacol. Exp. Ther., 274: 1362-1369, 1995). The purpose of the present study is to clarify the mechanisms for impairment of the biliary excretion of E3040 glucuronide in EHBR. We kinetically analyzed the disposition of the conjugates in the perfused liver at steady state. The uptake of the conjugates into the isolated canalicular membrane vesicles (CMVs) was also examined. At steady state, the bile/liver unbound concentration ratios of the conjugates were 40-400 in both rat strains, indicating a highly concentrated process. The biliary excretion clearance (CLu,bile) of the glucuronide, defined for the unbound concentration in the liver, was decreased in EHBR to 1/30 of that in normal rats, whereas the CLu,bile of the sulfate was comparable between the two rat strains. In vitro, the transport of E3040 glucuronide into CMV prepared from SD rats exhibited the ATP dependency, whereas minimal effect of ATP was observed on the uptake of the glucuronide into CMV from EHBR...Continue Reading

Citations

Oct 2, 1998·The American Journal of Physiology·H KusuharaY Sugiyama
Jun 21, 2001·Hypertension Research : Official Journal of the Japanese Society of Hypertension·H ShionoiriY Kawahara
Jul 19, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hao XiongMasahiko Negishi
Aug 9, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hao XiongKim L R Brouwer
Jul 26, 2006·Expert Opinion on Drug Metabolism & Toxicology·Gabriele JedlitschkyHeyo K Kroemer
Nov 22, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Maciej J Zamek-GliszczynskiKim L R Brouwer
Jan 27, 1998·The Journal of Biological Chemistry·K ItoY Sugiyama
Jun 11, 1999·The American Journal of Physiology·D F OrtizI M Arias
Apr 19, 2003·The Journal of Biological Chemistry·Michiko SuzukiYuichi Sugiyama
Apr 30, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Maciej J Zamek-GliszczynskiKim L R Brouwer
Jan 20, 2010·Drug Metabolism Reviews·Katalin JemnitzPeter Krajcsi
Oct 1, 1996·Digestive Diseases and Sciences·H TakikawaM Yamanaka
Nov 16, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Sanjay AwasthiYogesh C Awasthi
Jul 17, 2003·International Journal of Cancer. Journal International Du Cancer·Sanjay AwasthiYogesh C Awasthi
May 18, 1999·The American Journal of Physiology·K NiinumaY Sugiyama
Dec 10, 2002·Biochemical and Biophysical Research Communications·Hidetaka AkitaYuichi Sugiyama
Jan 28, 2004·European Journal of Pharmacology·Emiko AsakuraTakaaki Hasegawa
Feb 14, 2006·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Maciej J Zamek-GliszczynskiKim L R Brouwer

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