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

The effect of a liposomal formulation of methylprednisolone (MPL) on t he inhibition of lymphocyte proliferation in spleen cells was investig ated following IV dosing in rats. Liposomes do not alter the suppressi ve action of MPL when placed in lymphocyte culture. Rat splenocytes we re 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 d rug in solution. Animals were sacrificed at various times post-dosing until 120 h, spleen was excised and, after incubation of lymphocytes w ith PHA, splenocyte blastogenic responses were assessed by measuring c ellular incorporation of H-3-thymidine. The suppressive effect of lipo somal MPL in comparison with free drug was significantly prolonged (>1 20 h vs < 18 h). Inhibition effects versus time were described by a ph armacodynamic model using MPL concentrations in plasma as an input fun ction. A nonlinear relationship was found between suppression of splen ocyte proliferation and the concentration of bound glucocorticoid rece ptors in spleen. Only partial receptor occupancy accompanied complete lymphocyte suppression. The suppression of endogenous corticosterone i n plasma for both treatments was similar with values from L-MPL rats r eturning to baseline after 24 h. These results demonstrate enhanced ef ficacy of local immunosuppression by targeting spleen with liposomal M PL.