CLINICAL ASSESSMENT OF HERB-DRUG INTERACTION

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。40名受试者被分成两个独立的小组，每个小组包括相等数量的男性和女性(年龄在22-40岁)，他们将提供知情同意并被登记。第一组受试者(n=20)将用于评估慢性草药补充对肝脏和/或肠道细胞色素P3A4、细胞色素P1A2和细胞色素P2D6活性的影响(例如咪达唑仑，MDZ；咖啡因，CFE；和脱氢异喹，DB)。第二组(n=20)将用于评估草药补充剂是否可以调节P-gp活性(如地高辛、DGX)。两组受试者将分别接受草药、利福平和克拉霉素对CYP和P-gp活性的随机评估。每组的受试者将被随机分配到六个补充序列中的一个。要纳入这项研究，受试者必须健康状况良好，目前没有服用任何慢性药物或膳食补充剂。考生将向位于小石城约翰·L·麦克莱伦纪念退伍军人医院6楼的综合临床研究中心(GCRC)报告筛查程序。所有候选人将在病历、血液化学和尿液分析的帮助下进行筛选。排除标准包括：吸烟、长期饮酒、肥胖(&gt；120%理想体重)、口服避孕药使用、甲状腺功能异常、血清转氨酶升高、怀孕和哺乳期。在注册之前，受试者将用脱氢异喹(DB)进行表型鉴定，以筛选不良的CYP2D6代谢物。表现出不良代谢物表型(尿DB回收率？0.25)的受试者将被排除在外。受试者将被要求在清除和/或表型测量的前几天隔夜(~8小时)禁食。在学习日，所有受试者都将到位于阿肯色州小石城的约翰·L·麦克莱伦纪念退伍军人医院的综合临床研究中心报到。咪达唑仑(Versed10 mg口服液，罗氏实验室，新泽西州，Nutley，新泽西州)和地高辛(Lanoxicapers，两颗0.2 mg胶囊，葛兰素史克，北卡罗来纳州研究三角公园)将从商业来源获得，而Debrisquine(5 mg口服液)和咖啡因(100 mg口服液)将在UAMS药学院制备。在给药的每一天，将使用连续的血清和/或全血样本，或尿代谢物/母体比例来进行表型鉴定。这种方法的一个优点是，受试者充当自己的控制者。通过比较每个受试者在基线和治疗后清除/表型指数的差异，草药补充剂对CYP和P-gp活性的影响得到了最好的表征。以基线指数和治疗后指数之间的清除量差值计算的变化程度将使比较更加有效。例如，银杏叶对P-gp的后效最好通过比较基线和28天DGX清除量的差异来确定。该方法还控制了在探针药物清除度比较中固有的较大的受试者间变异性

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. Forty subjects divided into two independent groups, each containing equal numbers of males and females (aged 22-40 years), will provide informed consent and be enrolled. The first group of subjects (n = 20) will be used to evaluate the effect of chronic herb supplementation on hepatic and/or intestinal CYP3A4, CYP1A2, and CYP2D6 activity (e.g. midazolam, MDZ; caffeine, CFE; and debrisoquin, DB). The second group (n = 20) will be used to assess whether or not herbal supplements can modulate P-gp activity (e.g. Digoxin, DGX). Subjects in each of the two groups will undergo separate, randomized appraisals of herb, rifampin, and clarithromycin administration on CYP and P-gp activity. Subjects in each group will be randomized to one of six supplementation sequences. For inclusion in the study, subjects must be in good health and currently not on any chronic medication or dietary supplement. Candidates will report to the General Clinical Research Center (GCRC) located on the 6th floor of the John L. McClellan Memorial Veterans Hospital in Little Rock for screening procedures. All candidates will be screened with the aid of medical histories, blood chemistries and urinalyses. Exclusion criteria include: smoking, chronic alcohol intake, obesity (>120% ideal body weight), oral contraceptive use, abnormal thyroid function, elevated serum transaminases, pregnancy, and lactation. Prior to enrollment, subjects will be phenotyped with debrisoquine (DB) to screen for poor CYP2D6 metabolizers. Subjects exhibiting poor metabolizer phenotypes (urinary DB recovery ratio ? 0.25) will be excluded from participation. Subjects will be asked to fast overnight (~8 hours) prior to the days of clearance and/or phenotype measurement. On the study days, all subjects will report to the General Clinical Research Center at the John L. McClellan Memorial Veterans Hospital in Little Rock, AR. Midazolam (Versed10 mg oral solution, Roche Laboratories, Nutley, NJ), and digoxin (Lanoxicaps¿, two 0.2 mg capsules, Glaxo-Wellcome, Research Triangle Park, NC) will be obtained from commercial sources while debrisoquine (5 mg oral solution) and caffeine (100 mg oral solution) will be prepared at the UAMS College of Pharmacy. On each day of drug administration, serial serum and/or whole blood samples, or urinary metabolite/parent ratios will be used for phenotype characterization. An advantage of this approach is that subjects serve as their own control. By comparing the difference in baseline and post-treatment clearance/phenotype indices within each subject, the influence of herbal supplementation on CYP and P-gp activity is best characterized. The degree of change calculated as the difference in clearance between baseline and post-treatment indices will allow more effective comparisons. For example, the aftereffect of ginkgo biloba on P-gp is best determined by comparing differences in baseline and 28-day DGX clearances. This approach also controls for the large intersubject variability inherent in probe drug clearance comparisons