Prediction of Clinically Relevant Herb-Drug Clearance Interactions Using Sandwich-Cultured Human Hepatocytes: Schisandra spp. Case Study.

The Schisandraceae family is reported to have a range of pharmacological activities, including anti-inflammatory effects. As with all herbal preparations, extracts of Schisandra species are mixtures composed of >50 lignans, especially schizandrins, deoxyschizandrins, and gomisins. In China, Schisandra sphenanthera 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 Schisandra chinensis 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.