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/或改善对给药时间表的依从性。如果药物(S)和饮食物质(S)之间发生相互作用，这种传统的策略可能是有害的。目前，这种相互作用在很大程度上还没有被认识到。小红莓汁(CBJ)因其对健康的益处，包括预防尿路感染而被广泛宣传，是许多受欢迎的含果汁饮料的常见成分。最近有报道称，CBJ可显著增加大鼠体内CYP3A底物硝苯地平的全身暴露。CBJ抑制CYP3A介导的硝苯地平在肠道(但不是肝脏)的首过代谢，其作用与西柚汁(GFJ)相似。本申请中详述的初步数据表明，CBJ含有有效的肠溶型CYP3A4抑制剂。临床上显著的药物-GFJ相互作用是由于多种呋喃香豆素永久地使肠道中的CYP3A4失活，从而产生延长的抑制效应(~3天)。蔓越莓不是柑橘类水果，也不知道是否含有呋喃香豆素。因此，CBJ可能含有独特的作用机制未知的CYP3A4抑制剂。多个独立的实验室投入了大量的时间和资源来确定负责药物-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品化学家的组合专业知识，可以使用特征良好的体外人体肠道系统快速识别CBJ中活性的CYP3A4抑制剂。确定CBJ中主要的CYP3A4抑制剂将使CBJ标准化，使药物与CBJ相互作用的风险患者的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品。具体地说，在(1)评估了CBJ对人体肠道CYP3A4抑制程度的影响后，我们将使用人类肠道微生物体和表达CYP3A4的Caco-2细胞来(2)鉴定蔓越莓提取物中有效的CYP3A4抑制剂，以及(3)确定已鉴定的CYP3A4抑制剂的浓度和时间依赖的抑制特性。重要的是，这一新的实验范式可以广泛应用于识别其他天然化合物，这些化合物可以改变人体内的药物处置。拟议的翻译研究计划的长期目标是进一步从机制上理解饮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键信息，说明特定的饮食物质是否可以安全地与某些药物一起服用。

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.