CLINICAL ASSESSMENT OF HERB-DRUG INTERACTION

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。将40例受试者分为两个独立组，每组包含相同数量的男性和女性（年龄22-40岁），将提供知情同意书并入组。第一组受试者（n = 20）将用于评价长期草药补充对肝脏和/或肠道CYP 3A 4、CYP 1A 2和CYP 2D 6活性的影响（例如咪达唑仑，MDZ;咖啡因，CFE;和异氟喹，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（例如地高辛，DGX）。两组中的受试者将接受草药、利福平和克拉霉素给药对P-gp和P-gp活性的单独、随机评价。每组中的受试者将被随机分配至6个补充序列之一。入选研究的受试者必须健康状况良好，目前未接受任何慢性药物或膳食补充剂。候选人将向位于约翰L。麦克莱伦纪念退伍军人医院在小石城的筛选程序。所有候选人都将在病史、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（>理想体重的120%）、口服避孕药使用、甲状腺功能异常、血清转氨酶升高、妊娠和哺乳。入组前，将使用异喹胍（DB）对受试者进行表型分析，以筛选CYP 2D 6弱代谢者。表现出弱代谢者表型的受试者（尿DB回收率？0.25）将被排除在参与之外。要求受试者在清除和/或表型测量日之前空腹过夜（约8小时）。 在研究日，所有受试者将向约翰L。麦克莱伦纪念退伍军人医院在小石城，AR。 咪达唑仑（Versed 10 mg口服溶液，Roche Laboratories，Nutley，NJ）和地高辛（Lanoxicaps，2粒0.2 mg胶囊，Glaxo-Wellcome，Research Triangle Park，NC）将从商业来源获得，而异喹胍（5 mg口服溶液）和咖啡因（100 mg口服溶液）将在UAMS药学院制备。在给药的每一天，将使用系列血清和/或全血样本或尿代谢产物/母体药物比值进行表型表征。这种方法的一个优点是受试者作为自己的控制。通过比较每个受试者的基线和治疗后清除率/表型指数的差异，最好地表征了草药补充对P-gp和P-gp活性的影响。根据基线和治疗后指标之间的清除率差异计算的变化程度将允许进行更有效的比较。例如，银杏叶对P-gp的后效最好通过比较基线和28天DGX清除率的差异来确定。该方法还控制了探针药物清除率比较中固有的较大受试者间变异性

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