Genetic and Other Determinants of In Vivo CYP3A Activity

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION (provided by applicant): CYP3A is the most abundant of the human cytochrome P450 enzymes in both the intestine and liver. As a result, it is involved in the metabolism of over 50 percent of drugs and is an important determinant of first-pass metabolism following oral drug administration. Despite being metabolized by CYP3A, however, different substrates appear to interact with the enzyme in different ways, so that the metabolic clearance of one does not correlate with that of another. One hypothesis to account for this lack of correlation is that it reflects, in part, the different relative contributions of intestinal and hepatic CYP3A, and, thus, the route of drug administration. Drugs with different metabolic characteristics and routes of administration (midazolam, triazolam and alprazolam) will be used to test this hypothesis. A second possibility that will be investigated is that the CYP3A substrate-active site interaction is substrate-dependent, accordingly, drugs may be characterized into different "groups." Correlation within "groups" will, therefore, be present to a far greater extent than between "groups." In addition to the noted benzodiazepines, this hypothesis will be tested with other CYP3A substrates, such as cyclosporine-A, erythromycin and nifedipine, which are postulated to belong to other "groups." An important characteristic of CYP3A is marked interindividual variability in activity (10- to more than 40-fold), which significantly contributes to differences in drug responsiveness between subjects. A genetic determinant(s) is considered to be important in this regard but has never been formally defined and may, in fact, be different according to the tissue localization of CYP3A. Accordingly, the inheritability of CYP3A activity will be determined in monozygotic and dizygotic twins to test the hypothesis that a genetic factor is more important in regulating basal CYP3A-mediated metabolism in the liver than that in the intestine, and also in the enzyme?s inducibility at these two sites. Studies are also proposed which will establish the in vivo functional consequences of the allelic variants CYP3A4*1B and CYP3A5*3, and other known single nucleotide polymorphisms (SNPs). Finally, investigations in European-, African-American, and Japanese populations will be undertaken in order to identify SNPs associated with the interindividual variability in CYP3A activity.