In Vitro ADMET Laboratories, Inc., Columbia, Maryland
Drug Metab Dispos. 2020 Oct;48(10):980-992. doi: 10.1124/dmd.120.000053. Epub 2020 Jul 7.
Elements of key enteric drug metabolism and disposition pathways are reviewed to aid the assessment of the applicability of current cell-based enteric experimental systems for the evaluation of enteric metabolism and drug interaction potential. Enteric nuclear receptors include vitamin D receptor, constitutive androstane receptor, pregnane X receptor, farnesoid X receptor, liver X receptor, aryl hydrocarbon receptor, and peroxisome proliferator-activated receptor. Enteric drug metabolizing enzyme pathways include both cytochrome P450 (P450) and non-P450 drug metabolizing enzymes based on gene expression, proteomics, and activity. Both uptake and efflux transporters are present in the small intestine, with P-glycoprotein found to be responsible for most drug-drug and food-drug interactions. The cell-based in vitro enteric systems reviewed are 1) immortalized cell line model: the human colon adenocarcinoma (Caco-2) cells; 2) human stem cell-derived enterocyte models: stem cell enteric systems, either from intestinal crypt cells or induced pluripotent stem cells; and 3) primary cell models: human intestinal slices, cryopreserved human enterocytes, permeabilized cofactor-supplemented (MetMax) cryopreserved human enterocytes, and cryopreserved human intestinal mucosa. The major deficiency with both immortalized cell lines and stem cell-derived enterocytes is that drug metabolizing enzyme activities, although they are detectable, are substantially lower than those for the intestinal mucosa in vivo. Human intestine slices, cryopreserved human enterocytes, MetMax cryopreserved human enterocytes, and cryopreserved human intestinal mucosa retain robust enteric drug metabolizing enzyme activity and represent appropriate models for the evaluation of metabolism and metabolism-dependent drug interaction potential of orally administered xenobiotics including drugs, botanical products, and dietary supplements. SIGNIFICANCE STATEMENT: Enteric drug metabolism plays an important role in the bioavailability and metabolic fate of orally administered drugs as well as in enteric drug-drug and food-drug interactions. The current status of key enteric drug metabolism and disposition pathways and in vitro human cell-based enteric experimental systems for the evaluation of the metabolism and drug interaction potential of orally administered substances is reviewed.
元素的关键肠药物代谢和处置途径进行了回顾，以帮助评估当前基于细胞的肠实验系统的适用性评估肠道代谢和药物相互作用的潜力。肠核受体包括维生素 D 受体、组成型雄烷受体、孕烷 X 受体、法尼醇 X 受体、肝 X 受体、芳烃受体和过氧化物酶体增殖物激活受体。肠药物代谢酶途径包括细胞色素 P450（P450）和非 P450 药物代谢酶基于基因表达、蛋白质组学和活性。摄取和外排转运体都存在于小肠中，发现 P-糖蛋白是导致大多数药物-药物和食物-药物相互作用的原因。审查的基于细胞的体外肠系统是 1）永生化细胞系模型：人结肠腺癌（Caco-2）细胞；2）人类干细胞衍生的肠细胞模型：干细胞肠系统，无论是来自肠隐窝细胞还是诱导多能干细胞；3）原代细胞模型：人肠切片、冷冻保存的人肠细胞、透化补充辅助因子的（MetMax）冷冻保存的人肠细胞和冷冻保存的人肠黏膜。永生化细胞系和干细胞衍生的肠细胞的主要缺陷是，虽然可以检测到，但药物代谢酶活性明显低于体内肠黏膜。人肠切片、冷冻保存的人肠细胞、MetMax 冷冻保存的人肠细胞和冷冻保存的人肠黏膜保留了强大的肠药物代谢酶活性，是评估口服给予的外源性物质（包括药物、植物产品和膳食补充剂）的代谢和代谢依赖性药物相互作用潜力的合适模型。意义陈述：肠药物代谢在口服给予的药物的生物利用度和代谢命运以及肠药物-药物和食物-药物相互作用中起着重要作用。审查了当前关键肠药物代谢和处置途径以及用于评估口服给予物质代谢和药物相互作用潜力的基于人类细胞的体外肠实验系统的现状。
