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Research ArticleArticle

Correlation of Biliary Excretion in Sandwich-Cultured Rat Hepatocytes and In Vivo in Rats

Xingrong Liu, Jack P. Chism, Edward L. LeCluyse, Kenneth R. Brouwer and Kim L.R. Brouwer
Drug Metabolism and Disposition June 1999, 27 (6) 637-644;
Xingrong Liu
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Jack P. Chism
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Edward L. LeCluyse
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Kenneth R. Brouwer
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Kim L.R. Brouwer
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Abstract

The relationship between biliary excretion in sandwich-cultured rat hepatocytes and in vivo in rats was examined. The biliary excretion of seven model substrates in 96-h sandwich-cultured rat hepatocytes was determined by differential cumulative uptake of substrate in the monolayers preincubated in standard buffer (intact bile canaliculi) and Ca2+-free buffer (disrupted bile canaliculi). Biliary excretion in vivo was quantitated in bile duct-cannulated rats. The biliary excretion index of model substrates, equivalent to the percentage of retained substrate in the canalicular networks, was consistent with the percentage of the dose excreted in bile from in vivo experiments. The in vitro biliary clearance of inulin, salicylate, methotrexate, [d-pen2,5]enkephalin, and taurocholate, calculated as the ratio of the amount excreted into the bile canalicular networks and the area under the incubation medium concentration-time profile (∼0, ∼0, 4.1 ± 1.0, 12.6 ± 2.2, and 56.2 ± 6.0 ml/min/kg, respectively), correlated with their intrinsic in vivo biliary clearance (0.04, 0, 17.3, 34.4, and 116.9 ml/min/kg, respectively; r2 = 0.99). The model compound 264W94 was not excreted in bile either in vivo or in vitro. The glucuronide conjugate of 2169W94, theO-demethylated metabolite of 264W94, was excreted into bile in vitro when 2169W94, but not 264W94, was incubated with the monolayers; 2169W94 glucuronide undergoes extensive biliary excretion after administration of 264W94 or 2169W94 in vivo. Biliary excretion in long-term sandwich-cultured rat hepatocytes correlates with in vivo biliary excretion. The study of biliary excretion of metabolites in the hepatocyte monolayers requires consideration of the status of metabolic activities.

Footnotes

  • Send reprint requests to: Dr. Kim L.R. Brouwer, Pharm.D., Ph.D., Division of Drug Delivery and Disposition, School of Pharmacy, CB# 7360, Beard Hall, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360. E-mail: kbrouwer{at}unc.edu

  • This work was supported in part by National Institutes of Health Grant GM41935. X.L. was supported in part by a fellowship sponsored by Glaxo Wellcome, Inc.

  • Abbreviations used are::
    DMEM
    Dulbecco’s modified Eagle’s medium
    • Received July 9, 1998.
    • Accepted February 24, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (6)
Drug Metabolism and Disposition
Vol. 27, Issue 6
1 Jun 1999
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Research ArticleArticle

Correlation of Biliary Excretion in Sandwich-Cultured Rat Hepatocytes and In Vivo in Rats

Xingrong Liu, Jack P. Chism, Edward L. LeCluyse, Kenneth R. Brouwer and Kim L.R. Brouwer
Drug Metabolism and Disposition June 1, 1999, 27 (6) 637-644;

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Research ArticleArticle

Correlation of Biliary Excretion in Sandwich-Cultured Rat Hepatocytes and In Vivo in Rats

Xingrong Liu, Jack P. Chism, Edward L. LeCluyse, Kenneth R. Brouwer and Kim L.R. Brouwer
Drug Metabolism and Disposition June 1, 1999, 27 (6) 637-644;
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