Pharmacokinetics of prednisone and prednisolone at steady state in the rabbit
Unadkat, J.D.; Rowland, M.
Drug Metabolism and Disposition the Biological Fate of Chemicals 13(4): 503-509
1985
ISSN/ISBN: 0090-9556 PMID: 2863117 Document Number: 248752
A range (approximately 0.2-2.0 .mu.g/min per kg) of constant rate i.v. infusions of prednisolone (as the phosphate ester) was administered to 5 rabbits either singly or as two consecutive infusions, and then again at about the same rates of infusion as part of multiple infusion studies. Prednisone (as the succinate) was also infused at 3 different infusion rates (range, 1.5-15 .mu.g/min per kg) to 4 of the 5 rabbits. Plasma concentrations of prednisolone and prednisone at steady state were measured by HPLC [high-performance liquid chromatography]. The binding of prednisone and prednisolone in plasma was measured by equilibrium dialysis. The multiple infusion studies demonstrated that the nonlinearity in plasma clearance of prednisolone could not be attributed to any time-dependent effect. The average plasma clearance of prednisolone increased by 250% when its rate of infusion was increased 10-fold. The ranges of clearance values at low and high rates of infusion were 2.51-4.08 and 6.08-10.98 ml/min per kg, respectively. The binding of prednisolone in plasma was concentration-dependent. At the lower rates of infusions, the clearance of unbound prednisolone appeared to increase on increasing its rate of infusion but remained relatively constant thereafter (> 1.0 .mu.g/min per kg). The ranges of unbound plasma prednisolone clearance at low and high rates of infusions were 30.3-67.7 and 50.6-110.2 ml/min per kg, respectively. The percentage of unbound prednisone increased on increasing the total plasma prednisone concentration (ranges at low and high concentrations of prednisone were 15.5-33.7 and 32.3-47.6%). The availability of prednisone from its ester was not instantaneous. The nonlinear protein binding of prednisolone in plasma may not be the only factor responsible for the observed nonlinear pharmacokinetics of prednisolone in the rabbit.