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Research ArticleArticle

Sorafenib Hepatobiliary Disposition: Mechanisms of Hepatic Uptake and Disposition of Generated Metabolites

Brandon Swift, Noelia Nebot, Jin Kyung Lee, Tianxiang Han, William R. Proctor, Dhiren R. Thakker, Dieter Lang, Martin Radtke, Mark J. Gnoth and Kim L. R. Brouwer
Drug Metabolism and Disposition June 2013, 41 (6) 1179-1186; DOI: https://doi.org/10.1124/dmd.112.048181
Brandon Swift
Division of Pharmacotherapy and Experimental Therapeutics (B.S., N.N., J.K.L., D.R.T., K.L.R.B.), Division of Molecular Pharmaceutics (T.H., W.R.P.), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Drug Metabolism and Pharmacokinetics, Bayer Pharma AG, Wuppertal, Germany (D.L., M.R., M.J.G.)
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Noelia Nebot
Division of Pharmacotherapy and Experimental Therapeutics (B.S., N.N., J.K.L., D.R.T., K.L.R.B.), Division of Molecular Pharmaceutics (T.H., W.R.P.), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Drug Metabolism and Pharmacokinetics, Bayer Pharma AG, Wuppertal, Germany (D.L., M.R., M.J.G.)
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Jin Kyung Lee
Division of Pharmacotherapy and Experimental Therapeutics (B.S., N.N., J.K.L., D.R.T., K.L.R.B.), Division of Molecular Pharmaceutics (T.H., W.R.P.), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Drug Metabolism and Pharmacokinetics, Bayer Pharma AG, Wuppertal, Germany (D.L., M.R., M.J.G.)
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Tianxiang Han
Division of Pharmacotherapy and Experimental Therapeutics (B.S., N.N., J.K.L., D.R.T., K.L.R.B.), Division of Molecular Pharmaceutics (T.H., W.R.P.), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Drug Metabolism and Pharmacokinetics, Bayer Pharma AG, Wuppertal, Germany (D.L., M.R., M.J.G.)
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William R. Proctor
Division of Pharmacotherapy and Experimental Therapeutics (B.S., N.N., J.K.L., D.R.T., K.L.R.B.), Division of Molecular Pharmaceutics (T.H., W.R.P.), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Drug Metabolism and Pharmacokinetics, Bayer Pharma AG, Wuppertal, Germany (D.L., M.R., M.J.G.)
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Dhiren R. Thakker
Division of Pharmacotherapy and Experimental Therapeutics (B.S., N.N., J.K.L., D.R.T., K.L.R.B.), Division of Molecular Pharmaceutics (T.H., W.R.P.), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Drug Metabolism and Pharmacokinetics, Bayer Pharma AG, Wuppertal, Germany (D.L., M.R., M.J.G.)
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Dieter Lang
Division of Pharmacotherapy and Experimental Therapeutics (B.S., N.N., J.K.L., D.R.T., K.L.R.B.), Division of Molecular Pharmaceutics (T.H., W.R.P.), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Drug Metabolism and Pharmacokinetics, Bayer Pharma AG, Wuppertal, Germany (D.L., M.R., M.J.G.)
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Martin Radtke
Division of Pharmacotherapy and Experimental Therapeutics (B.S., N.N., J.K.L., D.R.T., K.L.R.B.), Division of Molecular Pharmaceutics (T.H., W.R.P.), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Drug Metabolism and Pharmacokinetics, Bayer Pharma AG, Wuppertal, Germany (D.L., M.R., M.J.G.)
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Mark J. Gnoth
Division of Pharmacotherapy and Experimental Therapeutics (B.S., N.N., J.K.L., D.R.T., K.L.R.B.), Division of Molecular Pharmaceutics (T.H., W.R.P.), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Drug Metabolism and Pharmacokinetics, Bayer Pharma AG, Wuppertal, Germany (D.L., M.R., M.J.G.)
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Kim L. R. Brouwer
Division of Pharmacotherapy and Experimental Therapeutics (B.S., N.N., J.K.L., D.R.T., K.L.R.B.), Division of Molecular Pharmaceutics (T.H., W.R.P.), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Drug Metabolism and Pharmacokinetics, Bayer Pharma AG, Wuppertal, Germany (D.L., M.R., M.J.G.)
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Abstract

Sorafenib is an orally active tyrosine kinase inhibitor used in the treatment of renal and hepatocellular carcinoma. This study was designed to establish whether transport proteins are involved in the hepatic uptake of sorafenib and to determine the extent of biliary excretion of sorafenib and its metabolites in human hepatocytes. Initial uptake was assessed in freshly isolated, suspended human hepatocytes in the presence of inhibitors and modulators. [14C]Sorafenib (1 µM) uptake at 4°C was reduced by about 61–63% of the uptake at 37°C, suggesting a high degree of passive diffusion. Hepatocyte uptake of [14C]sorafenib was not Na+ dependent or influenced by the organic anion transporter 2 inhibitor ketoprofen. However, initial [14C]sorafenib hepatocyte uptake was reduced by 46 and 30% compared with control values in the presence of the organic anion transporting polypeptide inhibitor rifamycin SV and the organic cation transporter (OCT) inhibitor decynium 22, respectively. [14C]Sorafenib (0.5–5 µM) uptake was significantly higher in hOCT1-transfected Chinese hamster ovary cells compared with mock cells, and inhibited by the general OCT inhibitor, 1-methyl-4-phenylpryidinium. OCT1-mediated uptake was saturable with a Michaelis-Menten constant of 3.80 ± 2.53 µM and a Vmax of 116 ± 42 pmol/mg/min. The biliary excretion index and in vitro biliary clearance of sorafenib (1 µM) in sandwich-cultured human hepatocytes were low (∼11% and 11 ml/min/kg, respectively). Results suggest that sorafenib uptake in human hepatocytes occurs via passive diffusion, by OCT1, and by organic anion transporting polypeptide(s). Sorafenib undergoes modest biliary excretion, predominantly as a glucuronide conjugate(s).

Footnotes

    • Received August 2, 2012.
    • Accepted March 12, 2013.
  • This research was supported by a grant from the National Institutes of Health [Grant R01GM41935]. B.S. was supported by an Eli Lilly and Company predoctoral fellowship.

  • This work was previously presented in part: Swift B, Nebot N, Lee JK, Proctor WR, Thakker DR, Lang D, Radtke M, Gnoth MJ, and Brouwer KLR (2010) Hepatic uptake and excretion of sorafenib and its metabolites. American Association of Pharmaceutical Scientists Annual Meeting; 2010 Nov 14–18; New Orleans, LA.

  • dx.doi.org/10.1124/dmd.112.048181.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (6)
Drug Metabolism and Disposition
Vol. 41, Issue 6
1 Jun 2013
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Research ArticleArticle

Sorafenib Hepatobiliary Disposition

Brandon Swift, Noelia Nebot, Jin Kyung Lee, Tianxiang Han, William R. Proctor, Dhiren R. Thakker, Dieter Lang, Martin Radtke, Mark J. Gnoth and Kim L. R. Brouwer
Drug Metabolism and Disposition June 1, 2013, 41 (6) 1179-1186; DOI: https://doi.org/10.1124/dmd.112.048181

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Research ArticleArticle

Sorafenib Hepatobiliary Disposition

Brandon Swift, Noelia Nebot, Jin Kyung Lee, Tianxiang Han, William R. Proctor, Dhiren R. Thakker, Dieter Lang, Martin Radtke, Mark J. Gnoth and Kim L. R. Brouwer
Drug Metabolism and Disposition June 1, 2013, 41 (6) 1179-1186; DOI: https://doi.org/10.1124/dmd.112.048181
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