Johnson Emily J, Won Christina S, Köck Kathleen, Paine Mary F
College of Pharmacy, Washington State University, Spokane, WA, USA.
Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, 07936, USA.
Biopharm Drug Dispos. 2017 Apr;38(3):251-259. doi: 10.1002/bdd.2061. Epub 2017 Feb 14.
Natural products, including botanical dietary supplements and exotic drinks, represent an ever-increasing share of the health-care market. The parallel ever-increasing popularity of self-medicating with natural products increases the likelihood of co-consumption with conventional drugs, raising concerns for unwanted natural product-drug interactions. Assessing the drug interaction liability of natural products is challenging due to the complex and variable chemical composition inherent to these products, necessitating a streamlined preclinical testing approach to prioritize precipitant individual constituents for further investigation. Such an approach was evaluated in the current work to prioritize constituents in the model natural product, grapefruit juice, as inhibitors of intestinal organic anion-transporting peptide (OATP)-mediated uptake. Using OATP2B1-expressing MDCKII cells (Madin-Darby canine kidney type II) and the probe substrate estrone 3-sulfate, IC were determined for constituents representative of the flavanone (naringin, naringenin, hesperidin), furanocoumarin (bergamottin, 6',7'-dihydroxybergamottin) and polymethoxyflavone (nobiletin and tangeretin) classes contained in grapefruit juice. Nobiletin was the most potent (IC , 3.7 μm); 6',7'-dihydroxybergamottin, naringin, naringenin and tangeretin were moderately potent (IC , 20-50 μm); and bergamottin and hesperidin were the least potent (IC , >300 μm) OATP2B1 inhibitors. Intestinal absorption simulations based on physiochemical properties were used to determine the ratios of unbound concentration to IC for each constituent within enterocytes and to prioritize in order of pre-defined cut-off values. This streamlined approach could be applied to other natural products that contain multiple precipitants of natural product-drug interactions. Copyright © 2016 John Wiley & Sons, Ltd.
天然产物，包括植物性膳食补充剂和异国风情饮品，在医疗保健市场中所占份额日益增加。与此同时，使用天然产物进行自我药疗的现象也越来越普遍，这增加了与传统药物同时服用的可能性，引发了人们对不良天然产物 - 药物相互作用的担忧。由于这些产品固有的化学成分复杂且多变，评估天然产物的药物相互作用风险具有挑战性，因此需要一种简化的临床前测试方法，以便对可能引发相互作用的单个成分进行优先排序，进而进行深入研究。在当前的研究中，对这种方法进行了评估，以便在模型天然产物葡萄柚汁中确定作为肠道有机阴离子转运多肽（OATP）介导摄取抑制剂的成分的优先级。使用表达OATP2B1的MDCKII细胞（II型马-达二氏犬肾细胞）和探针底物硫酸雌酮，测定了葡萄柚汁中黄烷酮（柚皮苷、柚皮素、橙皮苷）、呋喃香豆素（佛手柑内酯、6',7'-二羟基佛手柑内酯）和多甲氧基黄酮（川陈皮素和橘红素）类代表性成分的半数抑制浓度（IC）。川陈皮素是最有效的（IC，3.7μm）；6',7'-二羟基佛手柑内酯、柚皮苷、柚皮素和橘红素具有中等效力（IC，20 - 50μm）；而佛手柑内酯和橙皮苷是效力最弱的（IC，>300μm）OATP2B1抑制剂。基于理化性质的肠道吸收模拟用于确定肠细胞内各成分的未结合浓度与IC的比值，并根据预先定义的临界值进行优先级排序。这种简化方法可应用于其他含有多种天然产物 - 药物相互作用引发剂的天然产物。版权所有© 2016约翰威立父子有限公司。
