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

Pharm Res. 2013 Mar;30(3):761-80. doi: 10.1007/s11095-012-0918-y. Epub 2012 Nov 22.


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, IC(50) 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.

MeSH terms

  • Cyclosporine / metabolism
  • Cyclosporine / pharmacokinetics
  • Cyclosporine / pharmacology*
  • Cytochrome P-450 CYP3A / metabolism
  • Cytochrome P-450 CYP3A Inhibitors*
  • Drug Interactions
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • HEK293 Cells
  • Humans
  • Intestinal Mucosa / metabolism
  • Intestines / drug effects
  • Liver / drug effects
  • Liver / metabolism
  • Liver-Specific Organic Anion Transporter 1
  • Models, Biological
  • Organic Anion Transporters / antagonists & inhibitors*
  • Organic Anion Transporters / metabolism
  • Organic Anion Transporters, Sodium-Independent / antagonists & inhibitors*
  • Organic Anion Transporters, Sodium-Independent / metabolism
  • Solute Carrier Organic Anion Transporter Family Member 1B3


  • Cytochrome P-450 CYP3A Inhibitors
  • Enzyme Inhibitors
  • Liver-Specific Organic Anion Transporter 1
  • Organic Anion Transporters
  • Organic Anion Transporters, Sodium-Independent
  • SLCO1B1 protein, human
  • SLCO1B3 protein, human
  • SLCO2B1 protein, human
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Cyclosporine
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human