CONTRIBUTION OF INTESTINAL CYP3A TO FIRST PASS METABOLISM OF MIDAZOLAM

肠道 CYP3A 对咪达唑仑首过代谢的贡献

• 批准号: 6290943
• 负责人: STEPHEN D HALL
• 金额: $ 1.7万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6290943
• 关键词: clinical research; cytochrome P450; drug metabolism; human old age (65+); human subject; midazolam; pharmacokinetics; protein structure function

The cytochrome P450 3 A subfamily is comprisd of four genes CYP3A3, CYP3A4, CYP3A5, and CYP3A7; with CYP3A4 expressed in a majority of adult livers. Recently, CYP3A4 has been identified in enterocytes. Thus, intestinal CYP3A may play an important role in the oral bioabailability of CYP3A substrates such as midazolam, nifedipine,a nd cyclosporine A. Midazolam is a 1,4 imidazobenzodiazepine that exhibits a lower than expected oral bioavailability assuming that the liver is the sole organ of metabolism. A goal of this study is to determine the contribution of intestinal cytochrome P450 3A to the observed first pass metabolism of midazolam following oral administration using simultaneous intravenous and oral administration of midazolam and a stable isotope. A second goal of the study is to determine if clarithromycin inhibits the metabolism following oral administation at the intestinal or hepatic level.

细胞色素P450 3A亚家族由4个基因CYP 3A 3组成， CYP 3A 4、CYP 3A 5和CYP 3A 7; CYP 3A 4在大多数成人中表达 肝脏最近，已在肠上皮细胞中鉴定出CYP 3A 4。 因此，在本发明中， 肠道CYP 3A可能在口服生物利用度中起重要作用 CYP 3A底物，如咪达唑仑、硝苯地平和环孢菌素A。 咪达唑仑是一种1，4-咪唑并苯二氮杂卓， 假设肝脏是唯一的器官， 新陈代谢. 本研究的目的是确定 肠细胞色素P450 3A对观察到的 咪达唑仑口服给药后同时静脉和 口服咪达唑仑和稳定同位素。第二个目标是 该研究旨在确定克拉霉素是否抑制代谢， 在肠或肝水平口服给药后。