ONSET OF INHIBITORY EFFECT OF CLARITHROMYCIN ON HUMAN INTESTINAL CYTOCHROME P

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 克拉霉素是一种大环内酯类抗生素，是肝脏和小肠中细胞色素P450（CYP）3A酶的抑制剂。它增加了其他药物如环孢霉素、咪达唑仑、奥美拉唑和他克莫司的肝脏和肠道生物利用度。克拉霉素长期给药7天可使小肠CYP 3A活性降低74%。这种抑制的时间过程尚不清楚。本研究的目的是确定克拉霉素治疗7天期间人肠道CYP 3A活性的起效速度和最大抑制点。我们计划招募12名健康志愿者 并在基线和随后在开始克拉霉素治疗后6小时、2-4天、6-8天通过内窥镜检查获得十二指肠粘膜夹活检。我们期望通过测量粘膜夹取活检中的CYP 3A mRNA、蛋白质和活性来确定克拉霉素治疗期间肠道CYP 3A活性最大抑制的开始和时间。

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.