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Research ArticleArticle

Comparison of Intrinsic Clearance in Liver Microsomes and Hepatocytes from Rats and Humans: Evaluation of Free Fraction and Uptake in Hepatocytes

Chuang Lu, Ping Li, Richard Gallegos, Vinita Uttamsingh, Cindy Q. Xia, Gerald T. Miwa, Suresh K. Balani and Liang-Shang Gan
Drug Metabolism and Disposition September 2006, 34 (9) 1600-1605; DOI: https://doi.org/10.1124/dmd.106.010793
Chuang Lu
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Ping Li
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Richard Gallegos
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Vinita Uttamsingh
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Cindy Q. Xia
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Gerald T. Miwa
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Suresh K. Balani
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Liang-Shang Gan
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Abstract

Apparent intrinsic clearance (CLint,app) of 7-ethoxycoumarin, phenacetin, propranolol, and midazolam was measured using rat and human liver microsomes and freshly isolated and cryopreserved hepatocytes to determine factors responsible for differences in rates of metabolism in these systems. The cryopreserved and freshly isolated hepatocytes generally provided similar results, although there was greater variability using the latter system. The CLint,app values in hepatocytes are observed to be lower than that in microsomes, and this difference becomes greater for compounds with high CLint,app. This could partly be attributed to the differences in the free fraction (fu). The fu in hepatocyte incubations (fu,hep-inc) was influenced not only by the free fraction of compounds in the incubation buffer (fu,buffer) but also by the rate constants of uptake (kup) and metabolism (kmet). This report provides a new derivation for fu,hep-inc, which can be expressed as fu,hep-inc = [kup/(kmet + kup)]/[1 + (Chep/Cbuffer) × (Vhep/Vbuffer)], where the Chep, Cbuffer, Vhep, and Vbuffer represent the concentrations of a compound in hepatocytes and buffer and volumes of hepatocytes and buffer, respectively. For midazolam, the fu,hep-inc was calculated, and the maximum metabolism rate in hepatocytes was shown to be limited by the uptake rate.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.106.010793.

  • ABBREVIATIONS: CLint, intrinsic clearance; CLint,app, apparent intrinsic clearance; P450, cytochrome P450; LC/MS/MS, liquid chromatography coupled to tandem mass spectrometry; 7-EC, 7-ethoxycoumarin; fu,hep-inc, free fraction in hepatocyte incubations.

    • Received April 24, 2006.
    • Accepted June 19, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (9)
Drug Metabolism and Disposition
Vol. 34, Issue 9
1 Sep 2006
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Research ArticleArticle

Comparison of Intrinsic Clearance in Liver Microsomes and Hepatocytes from Rats and Humans: Evaluation of Free Fraction and Uptake in Hepatocytes

Chuang Lu, Ping Li, Richard Gallegos, Vinita Uttamsingh, Cindy Q. Xia, Gerald T. Miwa, Suresh K. Balani and Liang-Shang Gan
Drug Metabolism and Disposition September 1, 2006, 34 (9) 1600-1605; DOI: https://doi.org/10.1124/dmd.106.010793

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Research ArticleArticle

Comparison of Intrinsic Clearance in Liver Microsomes and Hepatocytes from Rats and Humans: Evaluation of Free Fraction and Uptake in Hepatocytes

Chuang Lu, Ping Li, Richard Gallegos, Vinita Uttamsingh, Cindy Q. Xia, Gerald T. Miwa, Suresh K. Balani and Liang-Shang Gan
Drug Metabolism and Disposition September 1, 2006, 34 (9) 1600-1605; DOI: https://doi.org/10.1124/dmd.106.010793
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