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: 6291096
• 负责人: STEPHEN D HALL
• 金额: $ 0.04万
• 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/6291096
• 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 comprised 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 bioavailability of CYP3A substrates such as midazolam, nifedipine,and 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亚家族由四个基因CYP 3A 3、CYP 3A 4、CYP 3A 5和CYP 3A 7组成;其中CYP 3A 4在大多数成人肝脏中表达。 最近，已在肠上皮细胞中鉴定出CYP 3A 4。 因此，肠道CYP 3A可能在CYP 3A底物（如咪达唑仑、硝苯地平和环孢素A）的口服生物利用度中发挥重要作用。咪达唑仑是一种1，4-咪唑并苯二氮卓类药物，假设肝脏是唯一的代谢器官，其口服生物利用度低于预期。 本研究的目的是确定肠细胞色素P450 3A对咪达唑仑口服给药后观察到的咪达唑仑首过代谢的贡献，同时静脉和口服给予咪达唑仑和稳定同位素。 本研究的第二个目的是确定克拉霉素在肠道或肝脏水平口服给药后是否抑制代谢。