This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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