A new animal model for testing renal tolerance of contrast agents.
OBJECTIVE
To develop a new animal model for the evaluation of the renal tolerance of contrast agent and its application to diatrizoate and iotrolan injections in comparison to saline and mannitol solution.


METHODS
The nephrotoxic potential of intravenously injected contrast agents in Beagle dogs was determined from the effects on the pharmacokinetics of creatinine injected immediately after these agents in comparison with the kinetics of creatinine injected alone. The kinetic parameters evaluated included plasma half-life, volume of distribution, and clearance. In a series of studies, the experimental conditions were optimized in terms of creatinine dose and the effects of diatrizoate, iotrolan, saline, and mannitol solution on the pharmacokinetic parameters of creatinine were determined.


RESULTS
Bolus injection of creatinine into dogs followed a dose-linear pharmacokinetic behavior with a terminal half-life of 90 minutes (10 mg/kg) and 108 minutes (20 mg/kg), respectively, and a clearance of 5 mL/min/kg. Injection of diatrizoate decreased the clearance and the half-life of creatinine significantly. A mannitol solution with the same osmolality as diatrizoate showed the same effect whereas physiological saline did not affect pharmacokinetic parameters of creatinine. The isotonic iotrolan was intermediate between saline and diatrizoate in its effects on creatinine clearance.


CONCLUSIONS
The effect of contrast agents on pharmacokinetic parameters of creatinine injected immediately after the administration of the agents in dogs might be a useful model for the evaluation of renal tolerance. In a cross-over study, iotrolan was not statistically separable from diatrizoate.
Krause
Werner
W
Research Laboratories of Schering AG, Berlin, Germany. werner.krause@schering.de
Gilles
Thomas
T
D000818:Animals; D003287:Contrast Media / Q000009:adverse effects*; D003404:Creatinine / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D003973:Diatrizoate / Q000009:adverse effects*; D004285:Dogs; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects*; D008353:Mannitol; D023421:Models, Animal; D009994:Osmolar Concentration; D012965:Sodium Chloride; D014283:Triiodobenzoic Acids / Q000009:adverse effects*
D003287:Contrast Media; D014283:Triiodobenzoic Acids; D003973:Diatrizoate; C033300:iotrolan; D008353:Mannitol; D012965:Sodium Chloride; D003404:Creatinine