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Research ArticleArticle

EMPIRICAL VALIDATION OF A RAT IN VITRO ORGAN SLICE MODEL AS A TOOL FOR IN VIVO CLEARANCE PREDICTION

Inge A. M. de Graaf, Ruben de Kanter, Marina H. de Jager, Raquel Camacho, Elise Langenkamp, Esther G. van de Kerkhof and Geny M. M. Groothuis
Drug Metabolism and Disposition April 2006, 34 (4) 591-599; DOI: https://doi.org/10.1124/dmd.105.006726
Inge A. M. de Graaf
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Ruben de Kanter
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Marina H. de Jager
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Raquel Camacho
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Elise Langenkamp
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Esther G. van de Kerkhof
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Geny M. M. Groothuis
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Abstract

Tissue slices have been shown to be a valuable tool to predict metabolism of novel drugs. However, besides the numerous advantages of their use for this purpose, some potential drawbacks also exist, including reported poor penetration of drugs into the inner cell layers of slices and loss of metabolic capacity during prolonged incubation, leading to underprediction of metabolic clearance. In the present study, we empirically identified (and quantified) sources of underprediction using rat tissue slices of lung, intestine, kidney, and liver and found that thin liver slices (±100 μm) metabolized model substrates (7-hydroxycoumarin, testosterone, warfarin, 7-ethoxycoumarin, midazolam, haloperidol, and quinidine) as rapidly as isolated hepatocytes. Furthermore, it was found that organ slices remain metabolically active for sufficient periods of incubation, enabling study of the kinetics of low clearance compounds. In addition, we determined the influence of albumin on the clearance prediction of six model substrates. For three of these substrates, the intrinsic clearance in the presence of albumin was approximately 3 times higher than that obtained from incubations without albumin, but corrected for unbound fraction. This resulted in a much more accurate prediction of in vivo whole body metabolic clearance for these compounds. Collectively, these results show that drawbacks of the use of slices for clearance prediction are largely surmountable. Provided that thin liver slices and physiological albumin concentration are used, whole body metabolic clearance is predicted with acceptable (2-fold) accuracy with organ slices. These results emphasize the applicability of organ slices in this field of research.

Footnotes

  • This study was supported by the Technology Foundation STW, Applied Science Division of NWO, and the Technology Program of the Ministry of Economic Affairs, and Yamanouchi Europe.

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

  • doi:10.1124/dmd.105.006726.

  • ABBREVIATIONS: 7-HC, 7-hydroxycoumarin; 7-EC, 7-ethoxycoumarin; L-15, Leibovitz's L-15 medium; WME, Williams' E medium; UW, University of Wisconsin organ preservation solution; BSA, bovine serum albumin; LC-MS, liquid chromatography/mass spectrometry; P450, cytochrome P450; CLint, intrinsic clearance; CLint,org, intrinsic metabolic organ clearance; CLorg, metabolic organ clearance; fu, unbound fraction.

    • Received July 29, 2005.
    • Accepted January 11, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (4)
Drug Metabolism and Disposition
Vol. 34, Issue 4
1 Apr 2006
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Research ArticleArticle

EMPIRICAL VALIDATION OF A RAT IN VITRO ORGAN SLICE MODEL AS A TOOL FOR IN VIVO CLEARANCE PREDICTION

Inge A. M. de Graaf, Ruben de Kanter, Marina H. de Jager, Raquel Camacho, Elise Langenkamp, Esther G. van de Kerkhof and Geny M. M. Groothuis
Drug Metabolism and Disposition April 1, 2006, 34 (4) 591-599; DOI: https://doi.org/10.1124/dmd.105.006726

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Research ArticleArticle

EMPIRICAL VALIDATION OF A RAT IN VITRO ORGAN SLICE MODEL AS A TOOL FOR IN VIVO CLEARANCE PREDICTION

Inge A. M. de Graaf, Ruben de Kanter, Marina H. de Jager, Raquel Camacho, Elise Langenkamp, Esther G. van de Kerkhof and Geny M. M. Groothuis
Drug Metabolism and Disposition April 1, 2006, 34 (4) 591-599; DOI: https://doi.org/10.1124/dmd.105.006726
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