title: The pharmacokinetics and acute renal effects of oral microemulsion ciclosporin A in normal pigs.
abstract: BACKGROUND
  The use of ciclosporin A (CsA) is limited by nephrotoxicity. Anatomic and physiologic similarities to humans make the pig a potential important animal model for research in effects and adverse events of CsA. In a long-term study CsA 10 mg/kg/day for 6 months did not cause deterioration in renal histology or function in pigs. For ideal CsA dosage in future long-term studies of nephrotoxicity we performed this study to describe pharmacokinetics and acute effects on renal function of CsA in normal pigs.
  
  
  METHODS
  Three groups of 5 piglets comprised the material, a control group and 2 groups receiving 5 days treatment with CsA (Neoral) 15 or 30 mg/kg/day, respectively. CsA whole blood concentration (B-CsA) (hourly), renal blood flow, glomerular filtration rate (GFR) and serum creatinine were measured. The area under the curve from time 0 to 12 h was calculated using the Trapezoidal Rule. Pharmacokinetic calculations were performed using the KINFIT non-linear curve fitting module.
  
  
  RESULTS
  B-CsA reached peak in median at 0.90 and 0.96 h (633 and 914 ng/ml) in the 15 and 30 mg/kg/day groups, respectively, and median AUC was 5055 and 6275 h ng/ml, respectively. Trough levels were 338 and 475 ng/ml. The distribution of CsA followed a 2-compartment model. Serum creatinine was 111 (control), 112 (15 mg/kg/day) and significantly increased to 168 ìmol/l in 30 mg/kg/day group, which also had a reduction in GFR compared to the other 2 groups.
  
  
  CONCLUSIONS
  CsA causes acute nephrotoxicity in piglets. The distribution follows a 2-compartment model similar to humans, but higher doses are necessary in pigs.
authors.affiliation: Clinical Institute, University of Aarhus Hospital, Skejby Sygehus, Denmark.
authors.forename: Donata
authors.initials: D
authors.lastname: Cibulskyte
authors.forename: Michael
authors.initials: M
authors.lastname: Pedersen
authors.forename: Jørgen
authors.initials: J
authors.lastname: Hjelm-Poulsen
authors.forename: Hans Erik
authors.initials: HE
authors.lastname: Hansen
authors.forename: Melvin
authors.initials: M
authors.lastname: Madsen
authors.forename: Jens
authors.initials: J
authors.lastname: Mortensen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004655:Emulsions; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects*; D007677:Kidney Function Tests; D012079:Renal Circulation / Q000187:drug effects; D013552:Swine
chemical_list: D004655:Emulsions; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003404:Creatinine