CYP3A ACTIVITY AND DRUG EFFECTS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 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 研究中心，而研究中心不一定是研究者所在的机构。 特异性P450亚型在药物代谢和清除中的作用可以使用体内探针来鉴定。 探针是某种P450亚型的选择性抑制剂，用于确定酶抑制（或在极少数情况下，诱导）对研究中特定药物处置的影响。 如果改变特定P450的活性改变了药物的处置，那么P450就被认为参与了该药物的处置。 已经为许多P450开发了体内探针。 噻氯匹定是一种抑制血小板聚集的药物，多年来一直在临床上用于预防动脉粥样硬化血栓形成事件，最近被确定为体外和体内人CYP 2B 6活性的选择性抑制剂。 探针的价值取决于其对单个P450的选择性。 抑制CYP 2B 6的化合物有时可抑制CYP 3A 4。 尽管噻氯匹定在体外对CYP 2B 6具有选择性，但其在体内对CYP 3A的活性尚不清楚。 本研究的目的是确定噻氯匹定对人体内CYP 3A活性的影响。 这将是一项在健康志愿者中进行的2阶段交叉研究，旨在确定噻氯匹定对阿芬太尼清除率的影响，这反映了CAP 3A的活性。

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 role of specific P450 isoforms in the metabolism and clearance of drugs can be identified using in vivo probes. Probes, which are selective inhibitors of a certain P450 isoform, are used to determine the effect of enzyme inhibition (or in rare cases, induction) on the disposition of the particular drug under investigation. If altering the activity of a specific P450 alters the disposition f the drug, then that P450 is said to be involved on the disposition of that drug. In vivo probes have been developed for many of the P450s. Ticlopidine, a drug that inhibits platelet aggregation and has been used clinically for several years for the prevention of atherothrombotic events, was recently identified as a selective inhibitor of human CYP2B6 activity in vitro and in vivo. The value of a probe depends upon its selectivity for a single P450. Compounds which inhibit CYP2B6 can sometimes inhibit CYP3A4. Although ticlopidine is selective for CYP2B6 in vitro, its activity on CYP3A in vivo is unknown. The purpose of this investigation is to determine the effect of ticlopidine on CYP3A activity in humans in vivo. This will be a 2-session crossover study in healthy volunteers, to determine the effect of ticlopidine on the clearance of alfentanil, which reflects the activity of CAP3A.