Objective: Although the human small intestine serves primarily as an absorptive organ for nutrients and water, it also has the ability to metabolise drugs. Interest in the small intestine as a drug-metabolising organ has been increasing since the realisation that it is probably the most important extrahepatic site of drug biotransformation.
Key findings: Among the metabolising enzymes present in the small intestinal mucosa, the cytochromes P450 (CYPs) are of particular importance, being responsible for the majority of phase I drug metabolism reactions. Many drug interactions involving induction or inhibition of CYP enzymes, in particular CYP3A, have been proposed to occur substantially at the level of the intestine rather than exclusively within the liver, as originally thought. CYP3A and CYP2C represent the major intestinal CYPs, accounting for approximately 80% and 18%, respectively, of total immunoquantified CYPs. CYP2J2 is also consistently expressed in the human gut wall. In the case of CYP1A1, large interindividual variation in the expression levels has been reported. Data for the intestinal expression of the polymorphic CYP2D6 are conflicting. Several other CYPs, including the common hepatic isoform CYP2E1, are expressed in the human small intestine to only a very low extent, if at all. The distribution of most CYP enzymes is not uniform along the human gastrointestinal tract, being generally higher in the proximal regions of the small intestine.
Summary: This article reviews the current state of knowledge of CYP enzyme expression in human small intestine, the role of the gut wall in CYP-mediated metabolism, and how this metabolism limits the bioavailability of orally administered drugs. Possible interactions between drugs and CYP activity in the small intestine are also discussed.