Pharmacokinetic characterization of a pig model of ciclosporin A nephrotoxicity following intravenous administration.
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.
Cibulskyte
Donata
D
Department of Renal Medicine, Skejby Hospital, Aarhus University Hospital, Aarhus, Denmark.
Pedersen
Michael
M
Jakobsen
Preben
P
Hansen
Hans Erik
HE
Mortensen
Jens
J
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
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003404:Creatinine