Comparison of Mouse and Rat Cytochrome P450-Mediated Metabolism in Liver and Intestine

Abstract

ABSTRACT:The liver is considered to be the major site of first-pass metabolism, but the small intestine is also able to contribute significantly. The improvement of existing in vitro techniques and the development of new ones, 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, compared with liver slices. Coincubation with ketoconazole inhibited the metabolic conversion in intestinal slices almost completely, but inhibition was variable in liver slices. 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, whereas CYP3A11, CYP3A25, and CYP3A41 are more expressed in the liver, comparable to similar findings in the rat.Altogether, 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.Although it is widely believed that the liver is the major site of first-pass metabolism, recent studies have indicated that the small intestine is able to contribute significantly to the overall first-pass metabolism of many drugs. Apart from the metabolic capacity, there are several other factors that play a role in the contribution of the intestine to the first-pass effect of drugs. First, the intestine is exposed to high concentrations of orally administered xenobiotics (Doherty and Charman, 2002). Second, anatomically, the small intestine has a serial relationship, with the liver in the process of absorption being the anterior organ. Third, in addition to drug-metabolizing enzymes such as cytochrome P450 (P450) isoenzymes, efflux proteins, such as P-glycoprotein and multidrug resistance-associated proteins, present in the apical membrane of the enterocytes, influence the metabolism process by recycling drugs between enterocytes and lumen, with the consequent higher drug exposure to intestinal metabolic enzymes (Doherty and Charman, 2002). Thus, the amount of an orally administered drug that reaches the systemic circulation can be reduced by both intestinal and hepatic metabolism. For some substrates, it has even been suggested that the role of intestinal metabolism is quantitatively greater than that of hepatic metabolism in the overall firstpass effect (Wu et al., 1995;Paine et al., 1996). Therefore, the important question is raised as to which factors determine the role of intestinal metabolism ...

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