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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 用于检测人类细胞色素 P4503A (CYP3A) 活性的理想体内探针仍然未知。 两种最常用且具有科学前景的探针是咪达唑仑和阿芬太尼的清除率。 清除率可能受到新陈代谢和/或肝血流量的影响。 阿芬太尼是一种低（或可能是中）提取药物，咪达唑仑是一种中提取药物。 根据常规理论，低提取物药物的清除率与肝血流无关，而中提取物药物的清除率则受肝血流影响。 然而，肝血流量对咪达唑仑和阿芬太尼清除率的影响尚未得到评估。 这项研究将检验以下假设：肝血流的改变不会对阿芬太尼的清除率产生影响，并且肝血流的改变对咪达唑仑的清除率的影响比对阿芬太尼的清除率的影响更大。 这项研究将在健康志愿者中上调和下调肝血流量，并评估对阿芬太尼和咪达唑仑的全身清除率和首过清除率的影响。 鉴定受肝血流影响较小的药物将有助于开发理想的 CYP3A 探针。