ONSET OF INHIBITORY EFFECT OF CLARITHROMYCIN ON HUMAN INTESTINAL CYTOCHROME P

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Clarithromycin is a macrolide antibiotic and is an inhibitor of Cytochrome P450 (CYP) 3A enzyme in the liver and small intestine. It increases the hepatic and intestinal bioavailability of other medications such as cyclosporine, midazolam, omeprazole, and tacrolimus. Chronic administration of clarithromycin for 7 days reduced small bowel CYP3A activity by 74%. The time course of this inhibition is unclear. The aim of this study is to determine the rapidity of the onset and point of maximal inhibition of human intestinal CYP3A activity during a 7 day course of clarithromycin treatment. We plan to enroll 12 healthy volunteers and obtain duodenal mucosal pinch biopsies by endoscopy at baseline and subsequently at 6 hrs, 2-4 days, 6-8 days after starting clarithromycin treatment. We expect to determine the onset and time of maximal inhibition of intestinal CYP3A activity during clarithromycin treatment by measuring CYP3A mRNA, protein and activity in the mucosal pinch biopsies.