Dextran-methylprednisolone succinate as a prodrug of methylprednisolone: dose-dependent pharmacokinetics in rats.

摘要

The dose-dependency in the pharmacokinetics of a macromolecular prodrug of methylprednisolone (MP), dextran-methylprednisolone succinate (DMP), was investigated in rats. Single doses (MP equivalent) of 2.5, 5.0, 10, 20, and 30 mg/kg of DMP were administered intravenously to rats (n=5/group), and serial blood samples (0-96 h) and spleen and liver tissues (96 h) were collected. The concentrations of DMP in plasma and spleen were analyzed using a size-exclusion chromatographic method. The concentrations of DMP in the liver samples were determined by an indirect method after sequential hydrolysis by dextranase and esterase enzymes, followed by HPLC analysis of MP. The kinetics of DMP were analyzed by non-compartmental methods. The systemic clearance of DMP decreased approximately 5-fold (from 42.1+/-11.0 to 7.72+/-1.84 ml/h per kg) when the dose was increased from 2.5 to 30 mg/kg. The nonlinearity in the clearance of DMP could be adequately described by a Michaelis-Menten type elimination with a maximum velocity of elimination of 1.72 mg/h per kg and a constant of 24.9 microg/ml. Additionally, the percent of the dose of DMP found at 96 h in the liver and spleen, where the prodrug is sequestered and gradually eliminated, significantly decreased with an increase in the dose. It is concluded that the clearance of DMP in rats is modestly dose-dependent in the dosage range of 2.5-30 mg/kg.