Mechanisms Underlying Drug-Diet Interactions

描述（由申请人提供）：许多患者在用餐时服用药物，以尽量减少副作用和/或提高对给药计划的依从性。如果药物和膳食物质之间发生相互作用，这种传统策略可能是有害的。目前，这种相互作用在很大程度上未被认识到。蔓越莓汁（CBJ）因其健康益处而被广泛宣传，包括预防尿路感染，是许多受欢迎的含果汁饮料的常见成分。最近有报道称，CBJ显著增加了大鼠体内CYP3A底物硝苯地平的全身暴露。CBJ抑制了硝苯地平的肠道（但不是肝脏）cyp3a介导的首过代谢，这种效果与葡萄柚汁（GFJ）相似。本应用中详细的初步数据表明，CBJ含有有效的肠溶性CYP3A4抑制剂。临床上重要的药物- gfj相互作用是由多种呋喃香豆素引起的，这些香豆素永久性地灭活肠内CYP3A4，从而引起长时间的抑制作用（约3天）。蔓越莓不是柑橘类水果，也不知道含有呋喃香豆素。因此，CBJ可能含有独特的CYP3A4抑制剂，其作用机制未知。多个独立实验室投入了大量的时间和资源来确定导致药物- gfj相互作用的有效成分。这一缓慢而昂贵的过程部分是由于缺乏多学科方法，以及缺乏相关体外系统的应用。我们假设一种多学科的转化研究方法，利用药物代谢科学家和天然产物化学家的综合专业知识，可以使用具有良好特征的人类肠道来源的体外系统快速识别CBJ中的活性CYP3A4抑制剂。识别CBJ中主要的CYP3A4抑制剂将允许有药物-CBJ相互作用风险的患者的CBJ标准化，并提供标记化合物来识别其他具有相互作用潜力的食物。具体来说，在(1)评估CBJ预处理对人类志愿者肠道中CYP3A4抑制程度的影响之后，我们将使用人类肠道微粒体和表达CYP3A4的Caco-2细胞来(2)鉴定蔓越莓提取物中有效的CYP3A4抑制剂，(3)确定所鉴定的CYP3A4抑制剂的浓度和时间依赖性抑制特性。重要的是，这种新的实验模式可以广泛应用于鉴定其他改变人体体内药物处置的天然化合物。拟议的转化研究计划的长期目标是进一步了解膳食物质对药物处置影响的机制。所获得的知识将为临床医生和普通公众提供关键信息，以确定特定膳食物质是否可以与某些药物一起安全服用。

DESCRIPTION (provided by applicant): Many patients take their medications with meals to minimize side effects and/or improve adherence to the administration schedule. This conventional strategy may be deleterious if an interaction occurs between the drug(s) and dietary substance(s). Currently, such interactions are largely unrecognized. Cranberry juice (CBJ), widely promoted for its health benefits, including prevention of urinary tract infections, is a common component of many popular juice-containing beverages. CBJ recently was reported to significantly increase the systemic exposure of the CYP3A substrate nifedipine in vivo in rats. CBJ inhibited the enteric (but not hepatic) CYP3A-mediated first-pass metabolism of nifedipine, an effect that mirrored that of grapefruit juice (GFJ). Preliminary data detailed in this application indicate that CBJ contains potent enteric CYP3A4 inhibitors. Clinically significant drug-GFJ interactions result from multiple furanocoumarins that inactivate enteric CYP3A4 permanently to elicit a prolonged inhibitory effect (~3 days). Cranberry is not a citrus fruit and is not known to contain furanocoumarins. Thus, CBJ likely contains unique CYP3A4 inhibitors with unknown mechanisms of action. Multiple independent laboratories have invested considerable time and resources in identifying the active ingredients responsible for drug-GFJ interactions. This slow, costly process was due in part to the lack of a multidisciplinary approach, combined with the lack of application of relevant in vitro systems. We hypothesize that a multidisciplinary translational research approach, which capitalizes on the combined expertise of drug metabolism scientists and natural products chemists, can rapidly identify the active CYP3A4 inhibitors in CBJ using well-characterized human intestine-derived in vitro systems. Identification of the major CYP3A4 inhibitors in CBJ would allow standardization of CBJs for patients at risk for drug-CBJ interactions, as well as provide marker compounds to identify other foods with interaction potential. Specifically, following (1) an evaluation of the effects of pretreatment of CBJ on the extent of enteric CYP3A4 inhibition in human volunteers, we will use human intestinal microsomes and CYP3A4-expressing Caco-2 cells to (2) identify potent CYP3A4 inhibitors in cranberry fractions and (3) define the concentration- and time-dependent inhibitory properties of the identified CYP3A4 inhibitors. Importantly, this novel experimental paradigm could be applied widely to identify additional natural compounds that alter drug disposition in humans in vivo. The long-term goal of the proposed translational research program is to further the mechanistic understanding of the effects of dietary substances on drug disposition. The knowledge gained will provide critical information to both clinicians and the lay public as to whether specific dietary substances can be taken safely with certain medications.