Dextran-methylprednisolone succinate as a prodrug of methylprednisolone: Immunosuppressive effects after in vivo administration to rats

Purpose. To study the immunosuppressive activities of a macromolecular prod rug of methylprednisolone (MP), dextran-methylprednisolone succinate (DEX-M PS), in rats. Methods. Single 5 mg/kg (MP equivalent) doses of MP or DEX-MPS were adminis tered intravenously to rats, and blood and spleen samples were collected ov er 96 h. The immunosuppressive activity was determined by the effects of th e free or dextran-conjugated drug on the mitogen-stimulated spleen lymphocy te proliferation. Additionally, the number of lymphocytes in the spleen cel l suspensions was estimated. Further, the plasma and spleen concentrations of the conjugated and free MP were determined using size-exclusion and reve rsed-phase chromatographic methods, respectively. Results. Both MP and DEX-MPS injections resulted in the inhibition of the s pleen lymphocyte proliferation. However, the maximal effect of DEX-MPS was significantly (P < 0.003) more intense (<similar to>100% inhibition) and de layed (24 h) relative to that of MP (similar to 50% inhibition at 2 h). The DEX-MPS injection also resulted in a significantly (P < 0.0001) higher dec line in the estimated number of spleen lymphocytes (<similar to>80% at 24 h ), compared with the MP injection (similar to 30% at 2hr). Whereas the plas ma and spleen concentrations of MP could not be measured at greater than or equal to2 h after the drug injection, relatively high concentrations of DE X-MPS persisted in plasma and spleen for 24 h and 96 h, respectively. Conclusion. Dextran-methylprednisolone conjugate can effectively deliver th e corticosteroid to its site of action for immunosuppression, resulting in more intense and sustained effects when compared with the free drug adminis tration.