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 prodrug of methylprednisolone (MP), dextran-methylprednisolone succinate (DEX-MPS), in rats.
METHODS: Single 5 mg/kg (MP equivalent) doses of MP or DEX-MPS were administered intravenously to rats, and blood and spleen samples were collected over 96 h. The immunosuppressive activity was determined by the effects of the free or dextran-conjugated drug on the mitogen-stimulated spleen lymphocyte proliferation. Additionally, the number of lymphocytes in the spleen cell suspensions was estimated. Further, the plasma and spleen concentrations of the conjugated and free MP were determined using size-exclusion and reversed-phase chromatographic methods, respectively.
RESULTS: Both MP and DEX-MPS injections resulted in the inhibition of the spleen lymphocyte proliferation. However, the maximal effect of DEX-MPS was significantly (P < 0.003) more intense (approximately 100% inhibition) and delayed (24 h) relative to that of MP (approximately 50% inhibition at 2 h). The DEX-MPS injection also resulted in a significantly (P < 0.0001) higher decline in the estimated number of spleen lymphocytes (approximately 80% at 24 h), compared with the MP injection (approximately 30% at 2 hr). Whereas the plasma and spleen concentrations of MP could not be measured at > or = 2 h after the drug injection, relatively high concentrations of DEX-MPS persisted in plasma and spleen for 24 h and 96 h, respectively.
CONCLUSION: Dextran-methylprednisolone conjugate can effectively deliver the corticosteroid to its site of action for immunosuppression, resulting in more intense and sustained effects when compared with the free drug administration.