title: Drug interaction between cyclosporine and mTOR inhibitors in experimental model of chronic cyclosporine nephrotoxicity and pancreatic islet dysfunction.
abstract: BACKGROUND
  It is known that sirolimus (SRL) aggravates cyclosporine A (CsA)-induced nephrotoxicity and pancreatic injury, but the influence of everolimus (EVR) on CsA-induced organ injury is undetermined.
  
  
  METHODS
  Rats were treated with CsA (15 mg/kg) and EVR or SRL (0.3 mg/kg) subcutaneously for 4 weeks. The influences of EVR or SRL on CsA-induced nephrotoxicity and pancreatic islet dysfunction were compared, and drug interactions between CsA and EVR or SRL were evaluated at blood and tissue levels.
  
  
  RESULTS
  Treatment with EVR or SRL alone did not cause severe pancreatic dysfunction and renal injury, but when combined with CsA they aggravated CsA-induced pancreatic and renal injury. Drug interactions between CsA and EVR or SRL differed at the tissue level. Combined treatment with CsA and SRL significantly increased the CsA or SRL levels in kidney and pancreas compared with CsA or SRL alone. However, combined treatment with CsA and EVR did not increase CsA or EVR levels in kidney and pancreas.
  
  
  CONCLUSIONS
  Both EVR and SRL aggravate CsA-induced organ injury, but the pharmacologic interaction between EVR and CsA at the tissue level is less than that between CsA and SRL. This finding provides better understanding of the difference between EVR and SRL when combined with CsA treatment.
authors.affiliation: Convergent Research Consortium for Immunologic Disease, The Catholic University of Korea, Seoul, Korea.
authors.forename: Shang Guo
authors.initials: SG
authors.lastname: Piao
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Bae
authors.forename: Sun Woo
authors.initials: SW
authors.lastname: Lim
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Song
authors.forename: Byung Ha
authors.initials: BH
authors.lastname: Chung
authors.forename: Bum Soon
authors.initials: BS
authors.lastname: Choi
authors.forename: Chul Woo
authors.initials: CW
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000068338:Everolimus; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D023421:Models, Animal; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus