CYP3A4 is one of the major drug metabolizing enzymes present in human liver and small bowel epithelial cells (enterocytes). The contribution of enterocyte CYP3A4 to drug elimination is believed to be substantial. However, distinguishing the contributions of the intestinal vs. the liver of this enzyme, as well as determining the role of the intestinal drug transporter P-glycoprotein, has been problematic. This study will test the hypothesis that some oral medication regimens that result in clinically important induction of CYP3A4 in liver do not induce the enzyme in the intestine. Groups of healthy volunteers will be treated for 14 days with therapeutic oral doses of one these clinically important inducers of liver CYP3A4: rifampin, phenobarbital, phenytoin, carbamazepine; or will receive no treatment. At four time points, subjects will receive the intravenous carbon-14 erythromycin breath test (a noninvasive test to measure liver CYP3A4 activity), undergo endoscopy to obtain small bowel biopsies and sigmoidoscopy to obtain colon biopsies. The times will be before drug dosing, after 2 days of dosing, after 7 days of dosing, and after 14 days of dosing.These studies should help clarify the role of the intestine in drug interactions involving CYP3A4 inducers. If demonstrated, selective induction of liver CYP3A4 may also be useful to help distinguish the roles of intestine and liver in the disposition of CYP3A4 substrates in people.
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