Jackson Jonathan P, Freeman Kimberly M, Friley Weslyn W, Herman Ashley G, Black Christopher B, Brouwer Kenneth R, Roe Amy L
Qualyst Transporter Solutions, Durham, North Carolina (J.P.J., K.M.F., W.W.F., A.G.H., C.B.B., and K.R.B.) and Procter & Gamble, Cincinnati, Ohio (A.L.R.)
Qualyst Transporter Solutions, Durham, North Carolina (J.P.J., K.M.F., W.W.F., A.G.H., C.B.B., and K.R.B.) and Procter & Gamble, Cincinnati, Ohio (A.L.R.).
Drug Metab Dispos. 2017 Sep;45(9):1019-1026. doi: 10.1124/dmd.117.075408. Epub 2017 Jul 11.
The Schisandraceae family is reported to have a range of pharmacological activities, including anti-inflammatory effects. As with all herbal preparations, extracts of species are mixtures composed of >50 lignans, especially schizandrins, deoxyschizandrins, and gomisins. In China, extract (SSE) is often coadministered with immunosuppressant treatment of transplant recipients. In cases of coadministration, the potential for herb-drug interactions (HDIs) increases. Clinical studies have been used to assess HDI potential of SSE. Results demonstrated that chronic SSE administration reduced midazolam (MDZ) clearance by 52% in healthy volunteers. Although clinical studies are definitive and considered the "gold standard," these studies are impractical for routine HDI assessments. Alternatively, in vitro strategies can be used to reduce the need for clinical studies. Transporter-certified sandwich-cultured human hepatocytes (SCHHs) provide a fully integrated hepatic cell system that maintains drug clearance pathways (metabolism and transport) and key regulatory pathways constitutive active/androstane receptor and pregnane X receptor (CAR/PXR) necessary for quantitative assessment of HDI potential. Mechanistic studies conducted in SCHHs demonstrated that SSE and the more commonly used dietary supplement extract (SCE) inhibited CYP3A4/5-mediated metabolism and induced CYP3A4 mRNA in a dose-dependent manner. SSE and SCE reduced MDZ clearance to 0.577- and 0.599-fold of solvent control, respectively, in chronically exposed SCHHs. These in vitro results agreed with SSE clinical findings and predicted a similar in vivo HDI effect with SCE exposure. These findings support the use of an SCHH system that maintains transport, metabolic, and regulatory functionality for routine HDI assessments to predict clinically relevant clearance interactions.
据报道，五味子科植物具有一系列药理活性，包括抗炎作用。与所有草药制剂一样，该科植物提取物是由50多种木脂素组成的混合物，尤其是五味子素、脱氧五味子素和戈米辛。在中国，五味子提取物（SSE）常与移植受者的免疫抑制治疗联合使用。联合用药时，草药-药物相互作用（HDI）的可能性增加。临床研究已用于评估SSE的HDI潜力。结果表明，在健康志愿者中，长期服用SSE可使咪达唑仑（MDZ）清除率降低52%。尽管临床研究具有决定性且被视为“金标准”，但这些研究对于常规HDI评估而言并不实用。另外，可以采用体外策略来减少临床研究的需求。经转运体认证的三明治培养人肝细胞（SCHHs）提供了一个完全整合的肝细胞系统，该系统维持药物清除途径（代谢和转运）以及定量评估HDI潜力所需的关键调节途径——组成型活性/雄甾烷受体和孕烷X受体（CAR/PXR）。在SCHHs中进行的机制研究表明，SSE和更常用的膳食补充剂水飞蓟提取物（SCE）以剂量依赖性方式抑制CYP3A4/5介导的代谢并诱导CYP3A4 mRNA表达。在长期暴露的SCHHs中，SSE和SCE分别将MDZ清除率降至溶剂对照的0.577倍和0.599倍。这些体外结果与SSE的临床研究结果一致，并预测SCE暴露在体内会产生类似的HDI效应。这些发现支持使用维持转运、代谢和调节功能的SCHH系统进行常规HDI评估，以预测临床相关的清除相互作用。
