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 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 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.
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