Drug Interactions and Bioavailability of Cranberry

蔓越莓的药物相互作用和生物利用度

• 批准号: 6751776
• 负责人: JENNIFER L DONOVAN
• 金额: $ 20.48万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-06 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6751776
• 关键词: alprazolam; alternative medicine; caffeine; clearance rate; clinical research; cytochrome P450; dextromethorphan; diet; diet therapy; drug metabolism; enzyme induction /repression; flavonoids; fruit; high performance liquid chromatography; human subject; nutrition related tag; patient oriented research; pharmacokinetics

DESCRIPTION (provided by applicant): Cranberry (CB) juice and powders are currently being used as complementary and alternative medications. CB products may be used alone or in combination with conventional medications to treat urinary tract infection, or other medications to treat acute or chronic conditions. CB is a rich source of flavonoids, a class of phytochemicals with diverse biological activities. The specific aims of this research are 1) to evaluate the potential for CB-drug interactions and 2) to determine the pharmacokinetics and renal clearance of four major CB flavonoids. A normal volunteer study is proposed to determine the potential of CB to participate in interactions with conventional drugs. The induction/inhibition of the major cytochrome P-450 (CYP) enzymes will be the primary method of evaluation. The CYP isoforms to be studied, CYP3A4, CYP2D6 and CYP1A2, are involved in the metabolism of >80% of marketed prescription and over the counter medications. Single doses of the three safe, probe drugs alprazolam (ALPZ; 3A4 probe), dextromethorphan (DM; CYP2D6 probe), and caffeine (CAF; CYP1A2 probe) will be administered at baseline (before treatment with CB) and after a 14-day treatment period with CB powder. Changes in the pharmacokinetics of these probe drugs will indicate the degree of specific enzyme inhibition or induction. In the same normal volunteers, the key pharmacokinetic parameters for four major CB flavonoids will be estimated by following the plasma concentration versus time course of absorbed flavonoids and their excretion in urine. The area under the plasma concentration versus time curve (AUC), oral clearance (Clo), terminal elimination half-life (T1/2) and renal clearance (Clren) will be determined for: epicatechin, quercetin (total glycosides), procyanidin A2, and cyanidin-3-galactoside. These components represent the major classes of flavonoids in CB and are selected for study due to their abundance in CB and their documented biological activities. The pharmacokinetics and renal clearance of CB flavonoids will be determined first after a single dose of a characterized CB juice prior to administration of any probe drugs. Steady-state plasma levels of flavonoids will be determined at the end of the 14-day treatment period of multiple dosing with the characterized CB powder. This research will provide new, important data on the pharmacokinetics of flavonoids from CB juice and from a CB powder, an area where no data currently exist. This information is essential to elucidate the mechanisms of action of CB flavonoids in the context of specific conditions/diseases and to evaluate CB as a source of dietary flavonoids. These data will also complement NCCAM studies assessing the clinical safety and efficacy of CB and will allow more informed recommendations about the use of CB when combined with conventional medications.

描述（由申请人提供）：蔓越莓（CB）果汁和粉末目前被用作补充和替代药物。CB产品可单独使用或与常规药物联合使用以治疗尿路感染，或与其他药物联合使用以治疗急性或慢性疾病。CB是黄酮类化合物的丰富来源，黄酮类化合物是一类具有多种生物活性的植物化学物质。本研究的具体目的是：1）评价CB-药物相互作用的可能性; 2）确定四种主要CB类黄酮的药代动力学和肾脏清除率。一个正常的志愿者研究建议，以确定潜在的CB参与与传统药物的相互作用。主要细胞色素P-450（CYP）酶的诱导/抑制将是主要评价方法。待研究的CYP 3A 4、CYP 2D 6和CYP 1A 2亚型参与>80%的市售处方药和非处方药的代谢。将在基线（CB治疗前）和CB粉末14天治疗期后单次给予三种安全的探针药物阿普唑仑（ALPZ; 3A 4探针）、美沙芬（DM; CYP 2D 6探针）和咖啡因（CAF; CYP 1A 2探针）。这些探针药物的药代动力学变化将指示特异性酶抑制或诱导的程度。在相同的正常志愿者中，通过跟踪吸收的黄酮类化合物的血浆浓度与时间过程及其在尿液中的排泄来估计四种主要CB黄酮类化合物的关键药代动力学参数。测定表儿茶素、槲皮素（总苷）、原花青素A2和矢车菊素-3-半乳糖苷的血浆浓度-时间曲线下面积（AUC）、口服清除率（Clo）、终末消除半衰期（T1/2）和肾清除率（Clren）。这些组分代表CB中黄酮类化合物的主要类别，并且由于它们在CB中的丰度和它们记录的生物活性而被选择用于研究。CB类黄酮的药代动力学和肾清除率将在施用任何探针药物之前在单剂量的表征的CB汁之后首先确定。将在14天多次给药表征CB粉末的治疗期结束时测定类黄酮的稳态血浆水平。这项研究将提供新的，重要的数据，黄酮类化合物的药代动力学从CB果汁和CB粉末，一个领域，目前还没有数据。这些信息对于阐明CB类黄酮在特定条件/疾病背景下的作用机制以及评估CB作为膳食类黄酮来源至关重要。这些数据还将补充NCCAM研究，评估CB的临床安全性和有效性，并将允许更明智的建议，当与常规药物联合使用CB。