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Drug Metabolism and Disposition Fast Forward
First published on March 24, 2006; DOI: 10.1124/dmd.105.009035

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Received for publication December 21, 2005.
Revised March 21, 2006.
Accepted for publication March 21, 2006.

Comparison of mouse and rat cytochrome P450 mediated metabolism in liver and intestine

Marcella Martignoni 1*, Geny Groothuis 2, Ruben de Kanter 3

1 Nerviano Medical Sciences 2 Groningen University Institute for Drug Exploration (GUIDE), Dept. Pharmacokinetics & Drug Delivery 3 Solvay Pharmaceuticals

* Address correspondence to: E-mail: marcella.martignoni{at}nervianoms.com

Abstract

The liver is considered to be the major site of first-pass metabolism, but also the small intestine is able to contribute significantly. The improvement of existing and the development of new in vitro techniques, such as intestinal slices, allow a better understanding of the intestine as a metabolic organ. In this paper, the formation of metabolites of several human CYP3A substrates by liver and intestinal slices from rat and mouse was compared. The results show that liver slices exhibited a higher metabolic rate for the majority of the studied substrates, but some metabolites were produced at a higher rate by intestinal slices, when compared with liver slices. Co-incubation with ketoconazole inhibited the metabolic conversion in intestinal slices almost completely but inhibition was variable in liver slices. In order to better understand the role of CYP3A in mice, we studied the relative mRNA expression of different CYP3A isoforms in intestine and liver from mice because in this species CYP3A expression has not been well described in these organs. It was found that in mice CYP3A13 is more expressed in the intestine, while CYP3A11, CYP3A25 and CYP3A41 are more expressed in the liver, comparable to similar findings in the rat. All together, these data demonstrate that, in addition to liver, the intestine from mouse and rat may have an important role in the process of first-pass metabolism, depending on the substrate. Moreover, we show that intestinal slices are a useful in vitro technique to study gut metabolism.


Key words: CYP3A, drug-drug interactions, extrahepatic cytochrome P450, extrahepatic drug metabolism, gastrointestinal cytochrome P450


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