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
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