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Research ArticleArticle

Metformin Sinusoidal Efflux from the Liver Is Consistent with Negligible Biliary Excretion and Absence of Enterohepatic Cycling

Maciej J. Zamek-Gliszczynski, Jing Q. Bao, Jeffrey S. Day and J. William Higgins
Drug Metabolism and Disposition November 2013, 41 (11) 1967-1971; DOI: https://doi.org/10.1124/dmd.113.053025
Maciej J. Zamek-Gliszczynski
Drug Disposition, Lilly Research Laboratories, Indianapolis, Indiana
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Jing Q. Bao
Drug Disposition, Lilly Research Laboratories, Indianapolis, Indiana
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Jeffrey S. Day
Drug Disposition, Lilly Research Laboratories, Indianapolis, Indiana
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J. William Higgins
Drug Disposition, Lilly Research Laboratories, Indianapolis, Indiana
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Abstract

Although metformin hepatic distribution is critical to pharmacological activity, the drug is cleared by urinary excretion. Metformin hepatobiliary disposition was studied in rodents representative of clinical pharmacokinetics to elucidate why metformin is not appreciably eliminated in bile. On average, 1.0% ± 0.1% of the metformin oral dose was present in the liver (liver/plasma ratio = 4.5 ± 0.6) over a pharmacologically relevant dose and time range in mice (10–300 mg/kg; 1.5–2.5 hours; Tmax = 1.4 ± 0.5; bioavailability > 59%). Distribution to the kidneys was not markedly higher, which contained 0.87% ± 0.08% of the oral dose (kidney/plasma ratio = 11.9 ± 1.1). However, only 0.11% ± 0.02% of the intravenous and bioavailable oral dose was recovered in bile, suggesting that biliary excretion is not the only route of clearance for hepatic metformin. Consistent with negligible biliary excretion, pharmacokinetics were unaffected by bile duct cannulation, proving the effective absence of enterohepatic cycling. In single-pass liver perfusion studies, 2.4% ± 0.3% of the perfused metformin dose was distributed to the liver, which underwent >300-fold greater sinusoidal than biliary excretion during the subsequent drug-free washout perfusion (74.0% ± 39.3% versus 0.222% ± 0.003% recovery of hepatic metformin in perfusate versus bile, respectively). These studies demonstrate that despite similar magnitude of metformin liver and kidney distribution, metformin biliary excretion is negligible due to predominant sinusoidal efflux from the liver.

Footnotes

    • Received May 22, 2013.
    • Accepted September 5, 2013.
  • dx.doi.org/10.1124/dmd.113.053025.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (11)
Drug Metabolism and Disposition
Vol. 41, Issue 11
1 Nov 2013
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Research ArticleArticle

Low Metformin Biliary Excretion Due to Sinusoidal Efflux

Maciej J. Zamek-Gliszczynski, Jing Q. Bao, Jeffrey S. Day and J. William Higgins
Drug Metabolism and Disposition November 1, 2013, 41 (11) 1967-1971; DOI: https://doi.org/10.1124/dmd.113.053025

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Research ArticleArticle

Low Metformin Biliary Excretion Due to Sinusoidal Efflux

Maciej J. Zamek-Gliszczynski, Jing Q. Bao, Jeffrey S. Day and J. William Higgins
Drug Metabolism and Disposition November 1, 2013, 41 (11) 1967-1971; DOI: https://doi.org/10.1124/dmd.113.053025
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