作者
Michael Gertz, Catherine M Cartwright, Michael J Hobbs, Kathryn E Kenworthy, Malcolm Rowland, J Brian Houston, Aleksandra Galetin
发表日期
2013/3
期刊
Pharmaceutical research
卷号
30
期号
3
页码范围
761-780
出版商
Springer US
简介
Purpose
To apply physiologically-based pharmacokinetic (PBPK) modeling to investigate the consequences of reduction in activity of hepatic and intestinal uptake and efflux transporters by cyclosporine and its metabolite AM1.
Methods
Inhibitory potencies of cyclosporine and AM1 against OATP1B1, OATP1B3 and OATP2B1 were investigated in HEK293 cells +/− pre-incubation. Cyclosporine PBPK model implemented in Matlab was used to assess interaction potential (+/− metabolite) against different processes (uptake, efflux and metabolism) in liver and intestine and to predict quantitatively drug-drug interaction with repaglinide.
Results
Cyclosporine and AM1 were potent inhibitors of OATP1B1 and OATP1B3, IC50 ranging from 0.019–0.093 μM following pre-incubation. Cyclosporine PBPK model predicted the highest …
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