Pharmacokinetics


Continued from page 69


6 Xin, HW et al (2009). Effects of Schisandra sphenanthera extract on the pharmacokinetics of midazolam in healthy volunteers. British J of Clinical Pharmacology, 67:5:541-546. 7 Hewitt, NJ, Lechón, MJG, Houston, JB et al. Primary hepatocytes: Current understanding of the regulation of metabolic enzymes and transporter proteins, and pharmaceutical practice for the use of hepatocytes in metabolism, enzyme induction, transporter, clearance, and hepatotoxicity studies. Drug Metab Rev, 2007:39;159-234. 8 Swift, B, Pfeifer, ND, Brouwer, KLR. Sandwich- cultured hepatocytes: An in vitro model to evaluate hepatobiliary transporter- based drug interactions and hepatotoxicity. Drug Metab Rev, 2010:42;446-471. 9 Jackson, et al (2017). Prediction of clinically-relevant herb-drug clearance interactions using sandwich- cultured human hepatocytes: Schisandra spp. case study. DMD, 45:1019-1026. 10 Backman, JT, Olkkola, KT and Neuvonen, PJ (1996). Rifampin drastically reduces plasma concentrations and effects of oral midazolam. Clin Pharmacol Ther, 59:7-13. 11Wang, Z, Gorski, JC, Hamman, MA, Huang, SM, Lesko, LJ and Hall, SD (2001). The effects of St John’s wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther, 70:317-326.


herbal inducer of CYP3A4, and were ≥73% of the rifampicin (RIF) treatment, a prototypical inducer of CYP3A49. To predict the overall clinical effect, evaluation


of midazolam intrinsic clearance following 72 hours of exposure demonstrated S. chinensis and S. sphenanthera both reduced midazolam clearance 35-40% and 42-48%, respectively (Figure 3 A-B). Our in vitro S. sphenanthera results were in remarkable agreement with a 52% decrease in clearance observed in clinical midazolam interac- tion studies. Additionally, our in vitro results were in good agreement with clinical-interaction studies of well-known perpetrators of in vivo drug interac- tions, SJW and RIF. In clinical drug-interaction studies, SJW and RIF increased midazolam clear- ance 2.0-fold and 24-fold, correspondingly10,11.


Conclusion Our retrospective case study demonstrated that an intrinsic clearance approach in sandwich-cultured human hepatocytes was feasible to evaluate net effect and relative strength of BDIs. We believe our ‘net-effect’ approach is an appropriate strategy to screen complex mixtures for drug interactions and can effectively predict in vivo BDIs at a much lower cost than clinical studies.


DDW


Dr Amy Roe is Principal Toxicologist at The Procter & Gamble Company. She has 20 years of experience as a toxicologist in government, phar- maceutical and consumer product industries. Her professional experience is in general and regulatory toxicology with specialised expertise in drug/xeno- biotic metabolism and pharmacokinetics.


Dr Jonathan Jackson is Senior Scientist, ADME- Tox at BioIVT. He has 12 years of experience in ADME-Tox working with pharmaceutical, con- sumer products, food additive and industrial chem- icals. His professional experience has primarily focused on human in vitro models with specific emphasis on metabolism, transport and gene regu- lation mechanisms which together play a signifi- cant role in drug/xenobiotic exposure, affecting absorption, elimination and toxicity.


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