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Molecular Pharmacology

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Research ArticleArticle

The Important Role of Bcrp (Abcg2) in the Biliary Excretion of Sulfate and Glucuronide Metabolites of Acetaminophen, 4-Methylumbelliferone, and Harmol in Mice

Maciej J. Zamek-Gliszczynski, Ken-ichi Nezasa, Xianbin Tian, J. Cory Kalvass, Nita J. Patel, Thomas J. Raub and Kim L. R. Brouwer
Molecular Pharmacology December 2006, 70 (6) 2127-2133; DOI: https://doi.org/10.1124/mol.106.026955
Maciej J. Zamek-Gliszczynski
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Ken-ichi Nezasa
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Xianbin Tian
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J. Cory Kalvass
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Nita J. Patel
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Thomas J. Raub
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Kim L. R. Brouwer
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Abstract

The role of Mrp2, Bcrp, and P-glycoprotein in the biliary excretion of acetaminophen sulfate (AS) and glucuronide (AG), 4-methylumbelliferyl sulfate (4MUS) and glucuronide (4MUG), and harmol sulfate (HS) and glucuronide (HG) was studied in Abcc2(-/-), Abcg2(-/-), and Abcb1a(-/-)/Abcb1b(-/-) mouse livers perfused with the respective parent compounds using a cassette dosing approach. Biliary clearance of the sulfate conjugates was significantly decreased in Bcrp-deficient mouse livers, resulting in negligible biliary excretion of AS, 4MUS, and HS. It is noteworthy that the most profound decrease in the biliary clearance of the glucuronide conjugates was observed in Bcrp-deficient mouse livers, although the biliary clearance of 4MUG was also ∼35% lower in Mrp2-deficient mouse livers. As expected, biliary excretion of conjugates was not impaired in P-glycoprotein-deficient livers. An appreciable increase in perfusate recovery due to a shift in the directionality of metabolite excretion, from bile to perfusate, was noted in knockout mice only for conjugates whose biliary clearance constituted an appreciable (≥37%) fraction of total hepatic excretory clearance (i.e., 4MUS, HG, and HS). Biliary clearance of AG, AS, and 4MUG constituted a small fraction of total hepatic excretory clearance, so an appreciable increase in perfusate recovery of these metabolites was not observed in knockout mice despite markedly decreased biliary excretion. Unlike in rats, where sulfate and glucuronide conjugates were excreted into bile predominantly by Mrp2, mouse Bcrp mediated the biliary excretion of sulfate metabolites and also played a major role in the biliary excretion of the glucuronide metabolites, with some minor contribution from mouse Mrp2.

Footnotes

  • This work was funded by National Institutes of Health grant R01-GM41935. M.J.Z.-G. was supported by an Eli Lilly and Company Foundation Predoctoral Fellowship in Pharmacokinetics and Drug Disposition.

  • These findings were presented in part at the 2005 American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition; Nov 6-10, 2005; Nashville, TN.

  • ABBREVIATIONS: SN-38, 7-ethyl-10-hydroxycamptothecin; AG, acetaminophen glucuronide; 4MUS, 4-methylumbelliferyl sulfate; 4MUG, 4-methylumbelliferyl glucuronide; HS, harmol sulfate; AS, acetaminophen sulfate; HG, harmol glucuronide; P-gp, P-glycoprotein; E3040, 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole; Clbasolateral, SS, steady-state basolateral excretory unbound intrinsic clearance; Clbile, SS, steady-state biliary unbound intrinsic clearance; Mrp, multidrug resistance-associated protein; Bcrp, breast cancer resistance protein.

  • ↵1 Current affiliation: Eli Lilly and Co., Drug Disposition, Indianapolis, IN.

  • ↵2 Current affiliation: Shionogi & Co., Ltd., Development Research Laboratories, Toyonaka, Osaka, Japan.

    • Received May 21, 2006.
    • Accepted September 6, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 70 (6)
Molecular Pharmacology
Vol. 70, Issue 6
1 Dec 2006
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Research ArticleArticle

The Important Role of Bcrp (Abcg2) in the Biliary Excretion of Sulfate and Glucuronide Metabolites of Acetaminophen, 4-Methylumbelliferone, and Harmol in Mice

Maciej J. Zamek-Gliszczynski, Ken-ichi Nezasa, Xianbin Tian, J. Cory Kalvass, Nita J. Patel, Thomas J. Raub and Kim L. R. Brouwer
Molecular Pharmacology December 1, 2006, 70 (6) 2127-2133; DOI: https://doi.org/10.1124/mol.106.026955

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Research ArticleArticle

The Important Role of Bcrp (Abcg2) in the Biliary Excretion of Sulfate and Glucuronide Metabolites of Acetaminophen, 4-Methylumbelliferone, and Harmol in Mice

Maciej J. Zamek-Gliszczynski, Ken-ichi Nezasa, Xianbin Tian, J. Cory Kalvass, Nita J. Patel, Thomas J. Raub and Kim L. R. Brouwer
Molecular Pharmacology December 1, 2006, 70 (6) 2127-2133; DOI: https://doi.org/10.1124/mol.106.026955
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