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Research ArticleArticle

Tissue Slices Revisited: Evaluation and Development of a Short-Term Incubation for Integrated Drug Metabolism

Sanjeev Thohan, MaryLynn C. Zurich, Ho Chung, Myron Weiner, Andrew S. Kane and Gerald M. Rosen
Drug Metabolism and Disposition October 2001, 29 (10) 1337-1342;
Sanjeev Thohan
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MaryLynn C. Zurich
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Ho Chung
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Myron Weiner
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Andrew S. Kane
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Gerald M. Rosen
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Abstract

This work details the development of a model for the rapid evaluation of drug metabolism in an integrated fashion using in situ architecture of the liver. A Krumdieck tissue slicer was used to generate slices from 10-mm cores of rat liver (approximately 250-μm thick). Initial unsuccessful efforts with 6-well plate-based incubation were overcome with the use of a dynamic (rotating) incubation in 23-ml liquid scintillation vials containing titanium mesh supports for the slice. Incubation of 1 slice/5 ml of a Krebs-Henseleit solution buffered with HEPES showed a <2% increase over the initial 25% release of lactate dehydrogenase over 2 h of incubation at 37°C under ambient oxygen conditions. CoupledO-dealkylase and conjugative metabolism of alkoxycoumarin derivatives was shown to be linear for both 7-methoxy- and 7-ethoxycoumarin (100 μM) with a low amount of nonconjugated 7-hydroxycoumarin (7-HC) at all time points. Metabolic profiles for 7-methoxy- and 7-ethoxycoumarin were compared between slice and microsomal incubations generated from the same tissue. The use of 7-HC as a primary substrate not only provided an assessment of the capacity-based differences in oxidative versus conjugative metabolism but also capacity-based differences in glucuronidation and sulfation. These studies underscore the physiological fact that phase I metabolism has a lower capacity for substrate metabolism than phase II metabolism. Additionally, this technique provides a model for examination of pharmacodynamic and pharmacokinetic influences in the context of maintenance of the in situ architecture of the liver.

Footnotes

  • Abbreviations used are::
    CYP
    cytochrome P450
    7-EC
    7-ethoxycoumarin
    7-HC
    7-hydroxycoumarin
    LDH
    lactate dehydrogenase
    7-MC
    7-methoxycoumarin
    IAA
    isoamyl alcohol mixture
    • Received February 15, 2001.
    • Accepted July 3, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (10)
Drug Metabolism and Disposition
Vol. 29, Issue 10
1 Oct 2001
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Research ArticleArticle

Tissue Slices Revisited: Evaluation and Development of a Short-Term Incubation for Integrated Drug Metabolism

Sanjeev Thohan, MaryLynn C. Zurich, Ho Chung, Myron Weiner, Andrew S. Kane and Gerald M. Rosen
Drug Metabolism and Disposition October 1, 2001, 29 (10) 1337-1342;

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Research ArticleArticle

Tissue Slices Revisited: Evaluation and Development of a Short-Term Incubation for Integrated Drug Metabolism

Sanjeev Thohan, MaryLynn C. Zurich, Ho Chung, Myron Weiner, Andrew S. Kane and Gerald M. Rosen
Drug Metabolism and Disposition October 1, 2001, 29 (10) 1337-1342;
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