title: Pharmacokinetic characterization of a pig model of ciclosporin A nephrotoxicity following intravenous administration.
abstract: BACKGROUND
  Recently, we investigated pharmacokinetics and acute nephrotoxicity of oral ciclosporin A (CsA) in pigs. We found that pigs require higher oral CsA doses to obtain comparable area under the concentration versus time curve (AUC) levels to renal transplant patients. The purpose of this study was to examine pharmacokinetics and possible acute renal effects of intravenous CsA in order to further characterize the pig as a model of CsA nephrotoxicity.
  
  
  METHODS
  Twenty-eight pigs were randomized into four groups: control and three groups subjected to a single CsA infusion at 3, 6, or 9 mg kg(-1). Blood samples for determination of whole blood CsA concentrations were collected over 7 h under general anaesthesia. At 0, 2, and 5 h, we measured blood pressure, serum creatinine, and haemoglobin, as well as renal blood flow (RBF), relative glomerular filtration rate (rGFR), and kidney volume using magnetic resonance imaging.
  
  
  RESULTS
  CsA distribution exhibited two-compartmental behaviour. Compared to renal transplant patients, pigs had approximately the same total clearance of CsA (mean 0.31-0.34lh(-1)kg(-1)), which yields comparable AUC after equivalent dosage in both species. However, the volume of distribution at steady state (mean 1.9-3.0lkg(-1)) was lower in pigs. RBF remained stable in all groups, whereas rGFR decreased in all groups reaching statistical significance in the controls.
  
  
  CONCLUSIONS
  Pigs require approximately the same intravenous CsA doses to obtain comparable total AUC to renal transplant patients. Single CsA infusion up to 9 mg kg(-1) for 1h has no deteriorating effect on renal haemodynamics and function.
authors.affiliation: Department of Renal Medicine, Skejby Hospital, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Donata
authors.initials: D
authors.lastname: Cibulskyte
authors.forename: Michael
authors.initials: M
authors.lastname: Pedersen
authors.forename: Preben
authors.initials: P
authors.lastname: Jakobsen
authors.forename: Hans Erik
authors.initials: HE
authors.lastname: Hansen
authors.forename: Jens
authors.initials: J
authors.lastname: Mortensen
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D007275:Injections, Intravenous; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000502:physiology; D008279:Magnetic Resonance Imaging; D011897:Random Allocation; D012079:Renal Circulation / Q000187:drug effects; D013552:Swine
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003404:Creatinine