CYP3A PROBES AND HEPATIC BLOOD FLOW

CYP3A 探针和肝血流

• 批准号: 7603355
• 负责人: Evan D. Kharasch
• 金额: $ 0.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2007-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7603355
• 关键词: Affect; Alfentanil; Blood flow; Computer Retrieval of Information on Scientific Projects Database; Cytochromes; Development; Funding; Grant; Hepatic; Human; Institution; Investigation; Liver; Metabolism; Midazolam; Pharmaceutical Preparations; Research; Research Personnel; Resources; Source; Testing; United States National Institutes of Health; healthy volunteer; in vivo; theories

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. The ideal in vivo probe for the activity of cytochrome P4503A (CYP3A) in humans remains unidentified. The two most commonly used and scientifically promising probes are the clearances of midazolam and alfentanil. Clearances may be influenced by metabolism and/or hepatic blood flow. Alfentanil is a low- (or possible intermediate-) extraction drug, and midazolam is an intermediate extraction drug. According to conventional theory, the clearance of low-extraction drugs is independent of hepatic bloodflow, while the clearance of intermediate-extraction drugs is affected by liver blood flow. However the effect of liver blood flow on the clearance of midazolam and alfentanil has not been evaluated. This investigation will test the hypothesis is that alteration in liver blood flow will have no effect on alfentanil clearance, and that alteration in liver blood flow will have a greater effect on midazolam clearance than on alfentanil clearance. This investigation, in healthy volunteers, will up-and down-regulate hepatic blood flow, and assess the effect on the systemic and first-pass clearances of alfentanil and midazolam. Identification of the drug which is less affected by liver blood flow will help towards the development of an ideal CYP3A probe.

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。 人体细胞色素P4503A(CyP3A)活性的理想活体探针仍未确定。最常用和最有科学前景的两种探针是咪达唑仑和阿芬太尼的清除剂。清除量可能受到代谢和/或肝脏血流的影响。阿尔芬太尼是一种低(或可能的中间)提取药物，咪达唑仑是一种中间提取药物。根据传统理论，低萃取物的清除与肝血流无关，而中间萃取物的清除受肝血流的影响。然而，肝血流对咪达唑仑和阿芬太尼清除的影响尚未得到评估。这项研究将检验这一假设，即肝脏血流的改变不会影响阿芬太尼的清除，而肝脏血流的变化对咪达唑仑的清除的影响将大于对阿芬太尼的清除的影响。这项在健康志愿者中进行的研究将上调和下调肝脏血流，并评估阿芬太尼和咪达唑仑对全身和首过清除的影响。对受肝脏血流影响较小的药物的鉴定将有助于开发理想的CYP3A探针。