Purpose. The purpose of this work was to study the local immunosuppressive effects of systemically administered methylprednisolone (MP) and its prodrug, dextran-methylprednisolone (DMP), in rat livers.
Methods. Single 5 mg/kg (MP equivalent) doses of MP or DMP were injected intravenously to rats, and livers were isolated at different time points (0-72 h; n = 4/time point). Isolated livers were stimulated ex vivo with bacterial lipopolysaccharide, and outlet perfusate and bile samples were analyzed for their concentrations of tumor necrosis factor (TNF)-α by enzyme-linked immunosorbent assay. The area under the perfusate TNF-α concentration-time curve (AUC) was used as a measure of immune response. Hepatic concentrations of MP and DMP were also measured by high-performance liquid chromatography.
Results. Both MP and DMP resulted in a decrease in lipopolysaccharide-induced increase in TNF-α AUC. MP injection 8 h before liver isolation resulted in a maximum of 50% decrease in TNF-α AUC. Compared with MP, the maximum effect of the prodrug (DMP) was both more intense (∼80% reduction in TNF-α AUC) and delayed (maximum inhibition at 24 h). Overall, the area under the effect (% inhibition of TNF-α)-time (%inhibition⋅h) for DMP (3680 ± 406) was approximately four times more than that for the parent drug (846 ± 114). Whereas the MP concentrations in the liver were not quantifiable after the injection of the parent drug, relatively large concentrations of DMP and regenerated MP were found in the liver of DMP-injected rats.
Conclusions. After systemic administration to rats, both MP and DMP exhibit local immunosuppressive effects in the liver. The local effects of the prodrug (DMP), however, appear to be more intense and sustained than those of the parent drug (MP).
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