Role of the Gut Mucosa in Metabolically Based Drug-Drug Interactions
The gastrointestinal mucosa represents a major physical and metabolic barrier to the systemic availability of orally ingested drug molecules. A critical component of that barrier is a collection of drug-metabolizing enzymes localized primarily at the apical aspect of the intestinal epithelium. The liver is generally considered to be the dominant site of drug metabolism, but it is now clear that for a number of drug molecules (e.g., midazolam, nifedipine, and verapamil), biotransformation at the intestinal mucosa contributes significantly to their first-pass removal. Indeed, some prodrugs have been developed that take advantage of the enzymatic activity of the intestinal mucosa (e.g., carboxyesterases and cytochromes P450) to promote the absorption and subsequent release of pharmacologically active drug into the hepatic portal circulation.