Pharmacokinetics


drug pharmacokinetics. We had the following goals: use a methodology that could treat a com- plex botanical mixture as a single entity, regardless of specific phytochemical constituents; utilise an in vitro tool that can study synergistic or competitive effects between phytochemical constituents; and design an experimental strategy that captures major clinically-relevant hepatic pathways and data output and makes direct predictions regarding clinical data. Thus, we chose to look at metabolic clearance changes of drugs using sandwich-cul- tured human hepatocytes exposed to botanical extracts. Our proof-of-concept study involved the use of Schisandra spp. with available in vitro and in vivo published data. Schisandra spp. have a wide range of purported


pharmacological activities including antioxidant, anti-inflammatory, antibacterial and cardio-pro- tection. S. chinensis is regulated as a dietary sup- plement in most geographies and S. sphenanthera is a marketed drug in China. In in vitro studies conducted by Iwata et al, various phytochemical constituents of S. chinensis were tested for the abil- ity to inhibit CYP450 activities4. The Gomisin class of constituents was shown to inhibit CYP3A4 with IC50 values as low as 0.257µM. The IC50 val-


Figure 2 Relative-fold change of


CYP3A4 mRNA content in sandwich-cultured human hepatocytes following 72 hours of treatment with RIF


(10mM), SJW (20mg/ml), SSE or SCE. Error bars represent 95% confidence intervals


ues observed were similar in potency to the known CYP3A4 inhibitor; ketoconazole. To date, there have been no clinical drug interaction studies con- ducted with S. chinensis. The related species, S. sphenanthera, has been studied in at least two clin- ical drug interaction studies. Xin et al studied the effects of S. sphenanthera extract on the pharma- cokinetics of tacrolimus in healthy volunteers, since this combination is often used in renal and liver transplant recipients in China5. The AUC of tacrolimus increased on average 164.2% following administration of S. sphenanthera. Similarly, these same researchers conducted a study in which S. sphenanthera was co-administered with midazo- lam6. In this study, AUC of midazolam was increased 119.4% after administration with S. sphenanthera. Based on these findings, we utilised the sand-


wich-cultured human hepatocytes in vitromodel to recapitulate the clinical findings of co-administra- tion of S. sphenanthera with midazolam. Furthermore, we wanted to conduct similar in vitro studies with co-treatments of S. chinensis and midazolam. Successful correlation of in vitro to in vivo findings between midazolam and S. sphenan- thera would provide confidence in extrapolating


68


Drug Discovery World Fall 2018


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