Drug Interactions and Bioavailability of Cranberry

描述(由申请人提供)：小红莓(CB)果汁和粉末目前正被用作补充和替代药物。CB产品可以单独使用，也可以与传统药物联合使用，用于治疗尿路感染，或与其他药物一起用于治疗急性或慢性疾病。CB富含黄酮类化合物，是一类具有多种生物活性的植物化学物质。这项研究的具体目的是：1)评估CB-药物相互作用的可能性；2)确定四种主要CB类黄酮类化合物的药代动力学和肾清除性。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。主要的细胞色素P-450(CYP)酶的诱导/抑制将是主要的评价方法。要研究的细胞色素P450亚型，即细胞色素P3A4、细胞色素P42D6和细胞色素P1A2，参与80%的上市处方药和非处方药的代谢。三种安全的探测药物阿普唑仑(ALPZ；3A4探测器)、右美沙芬(DM；CYP2D6探测器)和咖啡因(CAF；CYP1A2探测器)将在基线(CB治疗前)和CB粉末治疗14天后单次注射。这些探针药物的药代动力学变化将指示特定酶抑制或诱导的程度。在相同的正常受试者中，通过跟踪吸收的黄酮类化合物的血药浓度-时间过程及其在尿中的排泄，可以估计四种主要的CB类黄酮的关键药代动力学参数。血药浓度-时间曲线下面积(AUC)、口服清除量(CLO)、终末消除半衰期(T1/2)和肾清除量(Clren)将被确定为：表儿茶素、槲皮素(总苷)、原花青素A2和氰基-3-半乳糖苷。这些成分代表了CB中的主要类黄酮类化合物，并因其在CB中的丰富含量和已知的生物活性而被选为研究对象。在给予任何探测药物之前，首先将在单剂量的特征CB果汁之后测定CB黄酮类化合物的药代动力学和肾清除性。在多次给药的14天治疗期结束时，将测定具有特征的CB粉末的稳态血浆中类黄酮类的水平。这项研究将为CB果汁和CB粉末中的黄酮类化合物的药代动力学提供新的、重要的数据，这一领域目前还没有数据。这一信息对于阐明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评估CB临床安全性和有效性的研究，并将允许就CB与传统药物结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.