Mechanisms Underlying Drug-Diet Interactions

描述（由申请人提供）：许多患者随餐服用药物，以尽量减少副作用和/或提高对给药时间表的依从性。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没有得到承认。蔓越莓汁（CBJ）因其健康益处而被广泛推广，包括预防尿路感染，是许多流行的含果汁饮料的常见成分。最近报道CBJ可显著增加大鼠体内CYP 3A底物硝苯地平的全身暴露量。CBJ抑制肠道（但不是肝脏）CYP 3A介导的硝苯地平首过代谢，这一作用与葡萄柚汁（GFJ）相似。本申请中详细描述的初步数据表明，CBJ含有强效肠CYP 3A 4抑制剂。具有临床意义的药物-GFJ相互作用是由多种呋喃香豆素类药物引起的，这些呋喃香豆素类药物永久性地抑制肠道CYP 3A 4，从而引起延长的抑制作用（约3天）。蔓越莓不是柑橘类水果，也不含呋喃香豆素。因此，CBJ可能含有独特的CYP 3A 4抑制剂，作用机制未知。多个独立的实验室已经投入了大量的时间和资源来鉴定负责药物-GFJ相互作用的活性成分。这一缓慢、昂贵的过程部分是由于缺乏多学科方法，加上缺乏相关的体外系统的应用。我们假设，一个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，可以快速识别活性CYP 3A 4抑制剂在CBJ使用良好表征的人精氨酸衍生的体外系统。CBJ中主要CYP 3A 4抑制剂的鉴定将使处于药物-CBJ相互作用风险的患者的CBJ标准化，并提供标记化合物以鉴定具有相互作用潜力的其他食物。具体而言，在（1）评价CBJ预处理对人类志愿者肠道CYP 3A 4抑制程度的影响后，我们将使用人肠微粒体和表达CYP 3A 4的Caco-2细胞（2）鉴定蔓越莓组分中的强效CYP 3A 4抑制剂和（3）确定已鉴定CYP 3A 4抑制剂的浓度和时间依赖性抑制特性。重要的是，这种新的实验范式可以广泛应用于确定其他天然化合物，改变药物在人体内的处置。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的影响。所获得的知识将为临床医生和普通公众提供关于特定膳食物质是否可以与某些药物一起安全服用的关键信息。

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.