title: Cyclosporine inhibition of hepatic and intestinal CYP3A4, uptake and efflux transporters: application of PBPK modeling in the assessment of drug-drug interaction potential.
abstract: OBJECTIVE
  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.
authors.affiliation: Centre for Applied Pharmacokinetic Research School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, M13 9PT, Manchester, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Gertz
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Cartwright
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hobbs
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Kenworthy
authors.forename: Malcolm
authors.initials: M
authors.lastname: Rowland
authors.forename: J Brian
authors.initials: JB
authors.lastname: Houston
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Galetin
mesh_terms: D016572:Cyclosporine / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D008954:Models, Biological; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; C450859:SLCO2B1 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human