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Drug Metabolism and Disposition Fast Forward
First published on July 28, 2005; DOI: 10.1124/dmd.105.005686

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Received for publication May 25, 2005.
Revised July 27, 2005.
Accepted for publication July 27, 2005.

Characterisation of rat small intestinal and colon precision-cut slices as an in vitro system for drug metabolism and induction studies

Esther van de Kerkhof 1*, Inge de Graaf 1, Marina de Jager 1, Dirk Meijer 1, Geny Groothuis 1

1 Groningen University Institute for Drug Exploration

* Address correspondence to: E-mail: e.g.van.de.kerkhof{at}rug.nl

Abstract

The aim of this study was to characterise rat small intestinal and colon tissue slices as a tool to study intestinal metabolism and to investigate gradients of drug metabolism along the intestinal tract as well as drug-induced inhibition and induction of biotransformation. Tissue morphology and the intestinal mucus layer remained intact in small intestinal and colon slices during 3 hours of incubation, while alkaline phosphatase was retained and the rate of metabolism of three model compounds (7-hydroxycoumarin, 7-ethoxycoumarin and testosterone) appeared constant. Phase I and phase II metabolic gradients, decreasing from stomach towards colon were shown to be clearly different for the model compounds used. Furthermore, the observed slice activities were similar or even higher compared with the literature data concerning metabolism of in vitro intestinal systems. Pre-incubation with {beta}-naphtoflavone for 24 hours induced the O-deethylation of 7-ethoxycoumarin from nearly undetectable to 140 pmol/min/mg protein in small intestine (fresh slices: 43 pmol/min/mg protein) and to 100 pmol/min/mg protein in colon slices (fresh slices: undetectable). Ketoconazole inhibited metabolism of testosterone with 40% and of 7-ethoxycoumarin with 100%. In conclusion, we showed that the intestinal slice model is an excellent model to study drug metabolism in the intestine in vitro, since we found that the viability parameters remain constant and the measured enzyme activities are relevant, sensitive to inhibitors and inducible. Therefore, it is a promising tool to study intestinal drug metabolism in human intestine in vitro in the future.


Key words: CYP induction, extrahepatic drug metabolism, gastrointestinal cytochrome P450, phase II drug metabolism


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