Cyclosporine inhibition of hepatic and intestinal CYP3A4, uptake and efflux transporters: Application of PBPK Modeling in the assessment of drug-drug interaction potential

Research output: Contribution to journalArticle

  • External authors:
  • Michael Gertz
  • Catherine M. Cartwright
  • Michael J. Hobbs
  • Kathryn E. Kenworthy
  • Malcolm Rowland


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 interaction potential against liver uptake transporters, with a maximal reduction of >70% in OATP1B1 activity; the effect on hepatic efflux and metabolism was minimal. In contrast, 80-97% of intestinal P-gp and CYP3A4 activity was reduced due to the 50-fold higher cyclosporine enterocytic concentrations relative to unbound hepatic inlet. The inclusion of AM1 resulted in a minor increase in the predicted maximal reduction of OATP1B1/1B3 activity. Good predictability of cyclosporine-repaglinide DDI and the impact of dose staggering are illustrated. Conclusions: This study highlights the application of PBPK modeling for quantitative prediction of transporter-mediated DDIs with concomitant consideration of P450 inhibition. © 2012 Springer Science+Business Media New York.

Bibliographical metadata

Original languageEnglish
Pages (from-to)761-780
Number of pages19
JournalPharmaceutical Research
Issue number3
Publication statusPublished - Mar 2013