Noninvasive tests of CYP3A enzymes

Abstract

Cytochromes P450 belonging to the CYP 3A gene subfamily account for up to 2 5% of the total cyto­chrome P450 present in adult human liver, and account for the majority of cytochrome P450 present in human small bowel. The importance of the CYP3A enzymes is most established with respect to the metabolism of xenobiotics, particularly medications. The number of drugs metabolized chiefly by CYP3A enzymes is expanding rapidly and includes a wide variety of compounds in many different therapeutic classes (reviewed in Guengerich, 1992a; Watkins, 1992; Wrighton and Stevens, 1992). Several pharma­ceutical companies are now screening new chemical entities in development to determine whether they are metabolized by CYP3A enzymes. The finding that a drug is a substrate for CYP3A enzymes has three major implications. First, because CYP3A enzymes are relatively abundant in the intestinal mucosa (Kolars et al., 1992; Watkins et al., 198 7), CYP3A substrates may have poor oral bioavailability due to extensive 'first pass' metabolism at the level of the intestine (Kolars et al., 1991). Second, CYP3A substrates may be susceptible to certain drug interactions because some CYP3A enzymes are induced or inhibited by certain medications (reviewed in Watkins, 1992; Wrighton and Stevens, 1992). For example, the im­munosuppressant cyclosporine A and the antihis­tamine terfenadine have been shown to be metabolized chiefly by CYP3A4 (Kronbach et al., 1988; Combalbert et al., 1989; Chui-ho et al., 1993). This enzyme has been shown to be inhibited by erythromycin and ketoconazole (Pichard et al., 1990), and this appears to be the reason that patients receiving these drugs may develop toxic responses when treated with cyclosporine A or terfenadine. Conversely, CYP3A4 is inducible by treatment with antiseizure drugs and the antibiotic rifampicin (Pichard et al., 1990), and this appears to explain why patients treated with these medications require increased dosing of cyclosporine A. In drug development, the discovery that a new chemical entity is largely metabolized by CYP3A enzymes there­fore suggests the potential for similar drug inter­actions.