CYP3A PROBES AND HEPATIC BLOOD FLOW

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。用于检测人体细胞色素P4503 A（CYP 3A）活性的理想体内探针尚未确定。两种最常用和科学上最有前途的探针是咪达唑仑和阿芬太尼的清除率。清除率可能受代谢和/或肝血流量的影响。阿芬太尼是一种低（或可能的中间）提取药物，咪达唑仑是一种中间提取药物。传统理论认为，低提取率药物的清除与肝血流无关，而中提取率药物的清除受肝血流的影响。然而，肝血流量对咪达唑仑和阿芬太尼清除率的影响尚未进行评估。本研究将检验以下假设：肝血流量的改变对阿芬太尼清除率没有影响，肝血流量的改变对咪达唑仑清除率的影响大于对阿芬太尼清除率的影响。这项研究，在健康志愿者中，将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和首过清除率的影响。确定受肝血流影响较小的药物将有助于开发理想的CYP 3A探针。

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.