Drug Interactions and Bioavailability of Cranberry

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，用于治疗尿路感染，或用于治疗急性或慢性疾病的其他药物。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)评估四种主要的丁香叶类黄酮与药物相互作用的可能性；2)确定四种主要丁香叶类黄酮的药代动力学和肾清除率。建议进行一项正常的志愿者研究，以确定CB参与与常规药物相互作用的潜力。主要细胞色素P-450 （CYP）酶的诱导/抑制将是主要的评估方法。所研究的CYP3A4、CYP2D6和CYP1A2亚型参与了80%的已上市处方药和非处方药的代谢。三种安全的探针药物阿普唑仑（ALPZ； 3A4探针）、右美沙芬（DM； CYP2D6探针）和咖啡因（CAF； CYP1A2探针）将在基线（CB治疗前）和CB粉末治疗期14天后给予单剂量。这些探针药物的药代动力学变化将指示特定酶的抑制或诱导程度。在相同的正常志愿者中，通过观察四种主要的黄酮类化合物的血药浓度随吸收时间的变化，以及它们在尿液中的排泄情况，来估计四种主要黄酮类化合物的关键药动学参数。测定表儿茶素、槲皮素（总糖苷）、原花青素A2和花青素-3-半乳糖苷的血药浓度-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）。这些成分代表了黑炭黑中黄酮类化合物的主要类别，由于它们在黑炭黑中的丰度和已记录的生物活性而被选择进行研究。在给予任何探针药物之前，在单剂量具有特征的CB汁后，将首先确定CB类黄酮的药代动力学和肾脏清除率。在多次给药的14天治疗期结束时，测定黄酮类化合物的稳态血浆水平。本研究将为目前尚无相关数据的黑柱根汁和黑柱根粉中黄酮类化合物的药代动力学研究提供新的重要数据。这一信息对于阐明CB类黄酮在特定条件/疾病中的作用机制以及评估CB作为膳食类黄酮的来源至关重要。这些数据还将补充评估CB临床安全性和有效性的NCCAM研究，并将对CB与传统药物联合使用提出更明智的建议。

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.