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Molecular Pharmacology

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Research ArticleArticle

Phenobarbital Alters Hepatic Mrp2 Function by Direct and Indirect Interactions

Nita J. Patel, Maciej J. Zamek-Gliszczynski, Peijin Zhang, Yong-Hae Han, Peter L. M. Jansen, Peter J. Meier, Bruno Stieger and Kim L. R. Brouwer
Molecular Pharmacology July 2003, 64 (1) 154-159; DOI: https://doi.org/10.1124/mol.64.1.154
Nita J. Patel
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Maciej J. Zamek-Gliszczynski
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Peijin Zhang
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Yong-Hae Han
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Peter L. M. Jansen
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Peter J. Meier
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Bruno Stieger
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Kim L. R. Brouwer
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Abstract

Phenobarbital (PB) treatment impairs the biliary excretion of some organic anions. One mechanism may involve direct competition for biliary excretion by PB and/or a PB metabolite. Alternatively, PB may alter the expression and/or function of hepatic organic anion transport proteins. The role of multidrug resistance-associated protein 2 (Mrp2) in the biliary excretion of PB and metabolites was studied using isolated perfused livers (IPLs) from Wistar and Mrp2-deficient TR- rats. In normal livers, 4.19 ± 0.53% of the PB dose was recovered in bile as PB metabolites [2.21 ± 0.69% as 5-ethyl-5-(4-OH phenyl) barbituric acid (PBOH)-glucuronide; 1.98 ± 0.09% as PBOH-sulfate]. In TR- livers, only PBOH-sulfate was recovered in bile (0.35 ± 0.16% of dose) during the 2-h perfusion. Mrp2 message was increased (2.3-fold) by PB pretreatment (80 mg/kg i.p. × 4 days) but decreased to control values after a 48-h washout. Mrp2 protein was increased slightly in PB-treated livers and remained slightly elevated after a 24-h washout, but it was decreased significantly to 62 ±7% of control values after a 48-h washout. The 120-min cumulative biliary excretion of the Mrp2 substrate 5-(and-6)-carboxy-2′, 7′-dichlorofluorescein in IPLs from PB-treated rats after a 48-h washout was significantly lower than in vehicle-treated livers (66.3 ± 9.2% versus 83.4 ± 2.4% of the dose, respectively). These data support two mechanisms for impaired biliary excretion of some organic anions by PB treatment: 1) PBOH-glucuronide is a substrate for Mrp2 and may compete with other organic anions for biliary excretion and 2) Mrp2 protein expression and functional capacity is decreased 48 h after PB treatment.

  • Received December 24, 2002.
  • Accepted April 9, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 64 (1)
Molecular Pharmacology
Vol. 64, Issue 1
1 Jul 2003
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Research ArticleArticle

Phenobarbital Alters Hepatic Mrp2 Function by Direct and Indirect Interactions

Nita J. Patel, Maciej J. Zamek-Gliszczynski, Peijin Zhang, Yong-Hae Han, Peter L. M. Jansen, Peter J. Meier, Bruno Stieger and Kim L. R. Brouwer
Molecular Pharmacology July 1, 2003, 64 (1) 154-159; DOI: https://doi.org/10.1124/mol.64.1.154

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Research ArticleArticle

Phenobarbital Alters Hepatic Mrp2 Function by Direct and Indirect Interactions

Nita J. Patel, Maciej J. Zamek-Gliszczynski, Peijin Zhang, Yong-Hae Han, Peter L. M. Jansen, Peter J. Meier, Bruno Stieger and Kim L. R. Brouwer
Molecular Pharmacology July 1, 2003, 64 (1) 154-159; DOI: https://doi.org/10.1124/mol.64.1.154
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