In Vitro ADMET Laboratories Inc., Columbia, Maryland.
In Vitro ADMET Laboratories Inc., Columbia, Maryland
Drug Metab Dispos. 2020 Oct;48(10):1084-1091. doi: 10.1124/dmd.120.000033. Epub 2020 Jul 27.
Commercial formulations of 29 commonly used herbal supplements (HSs) and grapefruit juice were evaluated for drug interaction potential via quantification of their CYP3A inhibitory potential in two in vitro experimental models of human small intestine, cryopreserved human intestinal mucosa (CHIM), and cryopreserved human enterocytes (CHEs). Two CYP3A substrates were used-in the studies with CHIM, CYP3A activity was quantified via liquid chromatography tandem mass spectrometry quantification of midazolam 1'-hydroxylation, whereas in CHE, luciferin-IPA metabolism to luciferin was quantified by luminescence. Upon treatment of CHIM with the estimated lumen concentration of the HS upon each oral administration (manufacturers' recommended dosage dissolved in 200 ml of culture medium), >80% CYP3A inhibition was observed for green tea extract, St. John's wort, valerian root, horehound, and grapefruit juice. Less than 50% inhibition was observed for fenugreek, aloe vera, guarana, soy isoflavone, maca, echinacea, spirulina, evening primrose, milk thistle, cranberry, red yeast rice, rhodiola, ginkgo biloba, turmeric, curcumin, white kidney bean, garlic, cinnamon, saw palmetto berries, panax ginseng, black elderberry, wheat grass juice, flaxseed oil, black cohosh, and ginger root. The results were confirmed in a a dose-response study with HSs obtained from three suppliers for the four inhibitory HSs (green tea extract, horehound, St. John's wort, valerian root) and three representative noninhibitory HSs (black cohosh, black elderberry, echinacea). Similar results were obtained with the inhibitory HSs in CHE. The results illustrate that CHIM and CHE represent physiologically relevant in vitro experimental models for the evaluation of drug interaction potential of herbal supplements. Based on the results, green tea extract, horehound, St. John's wort, and valerian root may cause drug interactions with orally administered drugs that are CYP3A substrates, as was observed for grapefruit juice. SIGNIFICANCE STATEMENT: In vitro evaluation of 29 popular herbal supplements in cryopreserved human intestinal mucosa identified green tea extract, horehound, St. John's wort, and valerian root to have CYP3A inhibitory potential similar to that for grapefruit juice, suggesting their potential to have clinically significant pharmacokinetic interaction with orally administered drugs that are CYP3A substrates. The results suggest that cryopreserved human intestinal mucosa can be used for in vitro evaluation of drug interactions involving enteric drug metabolism.
评估了 29 种常用草药补充剂（HSs）和葡萄柚汁的商业制剂，通过在两种人类小肠的体外实验模型中定量其 CYP3A 抑制潜力来评估其药物相互作用的潜力，即冷冻保存的人类肠粘膜（CHIM）和冷冻保存的人类肠细胞（CHE）。使用了两种 CYP3A 底物-在 CHIM 的研究中，通过液相色谱串联质谱法定量咪达唑仑 1'-羟化来定量 CYP3A 活性，而在 CHE 中，通过发光定量荧光素-IPA 代谢为荧光素。在用每个口服给药的 HS 估计的腔浓度处理 CHIM 时（制造商推荐剂量溶解在 200 毫升培养基中），绿茶提取物、圣约翰草、缬草根、苦艾和葡萄柚汁观察到 >80%的 CYP3A 抑制。不到 50%的抑制作用观察到葫芦巴、芦荟、瓜拉那、大豆异黄酮、玛卡、紫锥菊、螺旋藻、月见草、奶蓟、蔓越莓、红曲米、红景天、银杏叶、姜黄、白芸豆、大蒜、肉桂、锯棕榈浆果、人参、黑接骨木、小麦草汁、亚麻籽油、黑升麻和姜根。在一项来自三个供应商的四种抑制性 HS（绿茶提取物、苦艾、圣约翰草、缬草根）和三种代表性非抑制性 HS（黑升麻、黑接骨木、紫锥菊）的 HS 剂量反应研究中证实了这一结果。在 CHE 中也观察到了类似的结果。结果表明，CHIM 和 CHE 代表了用于评估草药补充剂药物相互作用潜力的生理相关的体外实验模型。基于这些结果，绿茶提取物、苦艾、圣约翰草和缬草根可能会与口服给予的 CYP3A 底物药物发生药物相互作用，就像葡萄柚汁一样。意义声明：在冷冻保存的人类肠粘膜中对 29 种流行的草药补充剂进行的体外评估发现，绿茶提取物、苦艾、圣约翰草和缬草根具有与葡萄柚汁相似的 CYP3A 抑制潜力，表明它们有可能与口服给予的 CYP3A 底物药物发生具有临床意义的药代动力学相互作用。结果表明，冷冻保存的人类肠粘膜可用于涉及肠内药物代谢的药物相互作用的体外评估。
