DETERMINATION OF IN VIVO METABOLIC ACTIVATION OF CLOPIDOGREL

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。 这项研究旨在确定我们是否可以证明氯吡格雷(以Plavix的商标销售)主要是在哪里激活的。氯吡格雷是治疗和预防心脏病发作的重要药物。当冠心病患者服用这种药物时，它会停止血小板的活动，防止冠状动脉完全堵塞和心脏病发作。在最近的一项研究中，我们发现并非所有患者对氯吡格雷的反应都是相同的。换句话说，在一些患者中，氯吡格雷比其他患者更有效。在我们的研究中，对氯吡格雷的反应是通过血液测试来确定的，该测试测量了血小板聚集的百分比。包括氯吡格雷在内的许多药物需要一种酶(细胞色素P450 3A4)，这种酶在肝脏和小肠衬里的细胞中都存在，以便被代谢激活，使药物能够有效发挥作用。目前尚不清楚氯吡格雷是在肠壁细胞还是在肝脏中被代谢激活。这项研究旨在确定氯吡格雷的代谢激活主要是通过肠道的CYP3A4还是通过肝脏(肝脏系统)的CYP3A4。我们将使用红霉素，这是一种已知的肝脏CYP3A4抑制剂，以及西柚汁，它是一种已知的肠道CYP3A4抑制剂。当这些药物与氯吡格雷联合服用时，我们可以通过测试CYP3A4的活性来确定氯吡格雷的激活途径。在给予氯吡格雷和西柚汁后，将使用咪达唑仑的血药浓度来测量主要在小肠中对细胞色素P3A4活性的抑制。红霉素呼气试验将被用来测量给予红霉素后对肝脏中CYP3A4活性的抑制。咪达唑仑试验和红霉素呼气试验对于我们确定氯吡格雷在哪里代谢是必要的。这项研究招募了对氯吡格雷反应正常的成年人。参与者将被随机分配接受氯吡格雷和红霉素或氯吡格雷和西柚汁。如果红霉素(通过呼气试验测量)与氯吡格雷联合服用时，肝脏的CYP3A4活性被抑制，预计氯吡格雷的代谢激活将被抑制(对血小板的反应将减弱)，这将表明氯吡格雷在肝脏中被激活。另一方面，我们知道西柚汁是小肠中CYP3A4的抑制剂。如果用西柚汁(咪达唑仑试验测定)抑制肠道细胞色素P3A4活性，预计氯吡格雷的代谢激活将被抑制，这将表明氯吡格雷在肠道细胞膜上被激活。这项研究将招募30名对氯吡格雷反应正常的受试者。每个受试者将被随机分配到氯吡格雷和红霉素或氯吡格雷和西柚汁。将在方案中规定的特定时间点进行血液采样，以测量血小板功能和咪达唑仑水平。f给予西柚汁后，主要在小肠中进行细胞色素P3A4活性。。红霉素呼气试验将测量给予曲安霉素后，主要在肝脏中对CYP3A4活性的抑制。这两项测试对于我们确定氯吡格雷在哪里代谢是必要的。氯吡格雷抑制意味着当服用氯吡格雷时，血小板对氯吡格雷的反应不像没有西柚汁或曲莱雄霉素时那么有效。如果与氯吡格雷合用时，曲兰霉素(呼气试验测量)抑制肝脏细胞色素P3A4的活性，预计氯吡格雷的代谢激活将被抑制(对血小板的反应将减弱)，这表明氯吡格雷在肝脏中被激活。另一方面，我们知道西柚汁是小肠中细胞色素P3A4I‘的抑制剂。如果用西柚汁(咪达唑仑试验测定)抑制肠道细胞色素P3A4活性，预计氯吡格雷的代谢激活将被抑制，这将表明氯吡格雷在肠道细胞膜上被激活。 这项研究将招募30名对氯吡格雷反应正常的男性和女性，年龄在18-60岁之间，来自任何民族或种族。他们将被随机分配到氯吡格雷和曲霉素组或氯吡格雷和西柚汁组。将在每组不同的时间点进行血液测试，以确定氯吡格雷的激活部位。

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. This study is designed to determine if we can demonstrate where the medication clopidogrel (sold under the trade name of Plavix) is primarily activated. Clopidogrel is an important drug for the treatment and prevention of heart attacks. When patients with coronary artery disease take this drug, it stops the action of the platelets and prevents total coronary blockage and heart attacks. In a recent study we found that not all patients respond to clopidogrel the same way. In other words, in some patients clopidogrel was more effective than in others. In our studies, the response to clopidogrel is determined by a blood test that measures percent platelet clumping. Many drugs including clopidogrel require an enzyme (cytochrome P450 3A4), which is found in both the liver and the cells lining the small intestine, in order to be metabolically activated so the drugs can work effectively. It is not known whether clopidogrel is metabolically activated in the intestinal lining cells or in the liver. This study has been designed to determine whether the metabolic activation of clopidogrel is primarily by the intestinal CYP3A4 or by the CYP3A4 in the liver (hepatic system). We will use Erythromycin which is a known inhibitor of hepatic CYP3A4 and grapefruit juice which is a known inhibitor of intestinal CYP3A4. When these are taken in combination with clopidogrel, we can determine the route of activation of clopidogrel by doing tests that measure the activity of CYP3A4. Blood levels of midazolam will be used to measure the inhibition of CYP3A4 activity primarily in the small intestine after clopidogrel and grapefruit juice is given. The erythromycin breath test will be used to measure the inhibition of CYP3A4 activity primarily in the liver after Erythromycin is given. Both the midazolam test and the erythromycin breath test are necessary for us to determine where clopidogrel is metabolized. This study recruits adults who respond normally to clopidogrel. Participants will be randomly assigned to receive either clopidogrel and Erythromycin or clopidogrel and grapefruit juice. If the hepatic CYP3A4 activity is inhibited by Erythromycin (as measured by the breath test) when taken in combination with clopidogrel, it is expected that metabolic activation of clopidogrel will be inhibited (response on platelets will be diminished) and would indicate that clopidogrel is activated in the liver. On the other hand, we know that grapefruit juice is an inhibitor of CYP3A4 in the small intestine. If the intestinal CYP3A4 activity is inhibited by grapefruit juice (which is determined by the midazolam test) it is expected that metabolic activation of clopidogrel will be inhibited and would indicate that clopidogrel is activated in the intestinal cell lining. This study will recruit 30 subjects who respond normally to clopidogrel. Each subject will be randomly assigned equally to either the clopidogrel and Erythromycin or clopidogrel and grapefruit juice. Blood sampling will be performed at specific timepoints outlined in the protocol to measure platelet function and to measure levels of midazolam.f CYP3A4 activity primarily in the small intestine after grapefruit juice is given. . The erythromycin breath test will measure the inhibition of CYP3A4 activity primarily in the liver after troleandomycin is given. Both of these tests are necessary for us to determine where clopidogrel is metabolized. Clopidogrel inhibition means that when taken, the response of the platelets to clopidogrel is not as effective as it would be without the grapefruit juice or troleandomycin. If the hepatic CYP3A4 activity is inhibited by troleandomycin (measured by the breath test) when taken in combination with clopidogrel, it is expected that metabolic activation of clopidogrel will be inhibited (response on platelets will be diminished) and would indicate that clopidogrel is activated in the liver. On the other hand, we know that grapefruit juice is an inhibitor of CYP3A4 i'n the small intestine. If the intestinal CYP3A4 activity is inhibited by grapefruit juice (which is determined by the midazolam test) it is expected that metabolic activation of clopidogrel will be inhibited and would indicate that clopidogrel is activated in the intestinal cell lining. This study will recruit 30 males and females aged 18-60 of any ethnic origin or race who respond normally to clopidogrel. They will be randomly assigned equally to either the clopidogrel and troleandomycin group or clopidogrel and grapefruit juice group. Blood tests will be performed in various time points in each group to determine the site of activation of clopidogrel.