ONSET OF INHIBITORY EFFECT OF CLARITHROMYCIN ON HUMAN INTESTINAL CYTOCHROME P

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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。它增加了其他药物的肝脏和肠道生物利用度，如环孢素、咪达唑仑、奥美拉唑和他克莫司。长期服用克拉霉素7d后，小鼠小肠细胞色素P3A活性下降74%。这种抑制的时间进程尚不清楚。本研究的目的是确定克拉霉素治疗7天期间人体肠道细胞色素P3A活性最大抑制的起始点和起始点的快慢。我们计划招募12名健康志愿者，在基线和随后的克拉霉素治疗后6小时、2-4天、6-8天通过内窥镜进行十二指肠黏膜夹活检。我们期望通过检测粘膜活检组织中的细胞色素P3A的mRNA、蛋白和活性来确定在克拉霉素治疗期间肠道细胞色素P3A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.