INHIBITION OF RAT SPLENOCYTE PROLIFERATION WITH METHYLPREDNISOLONE - IN-VIVO EFFECT OF LIPOSOMAL FORMULATION

The effect of a liposomal formulation of methylprednisolone (MPL) on the inhibition of lymphocyte proliferation in spleen cells was investigated following IV dosing in rats. Liposomes do not alter the suppressive action of MPL when placed in lymphocyte culture. Rat splenocytes were found to have greater sensitivity to MPL (ECS(50) = 7.9 nM) than do human peripheral blood lymphocytes (EC(50) = 28 nM). In vivo studies in rats utilized 2 mg/kg IV bolus doses of liposomal MPL compared to drug in solution. Animals were sacrificed at various times post-dosing until 120 h, spleen was excised and, after incubation of lymphocytes with PHA, splenocyte blastogenic responses were assessed by measuring cellular incorporation of H-3-thymidine. The suppressive effect of liposomal MPL in comparison with free drug was significantly prolonged (>120 h vs < 18 h). Inhibition effects versus time were described by a pharmacodynamic model using MPL concentrations in plasma as an input function. A nonlinear relationship was found between suppression of splenocyte proliferation and the concentration of bound glucocorticoid receptors in spleen. Only partial receptor occupancy accompanied complete lymphocyte suppression. The suppression of endogenous corticosterone in plasma for both treatments was similar with values from L-MPL rats returning to baseline after 24 h. These results demonstrate enhanced efficacy of local immunosuppression by targeting spleen with liposomal MPL.