Spinal cord bioavailability of methylprednisolone after intravenous and intrathecal administration - The role of P-glycoprotein

Background: High-dose intravenously administered methylprednisolone has bee n shown to improve outcome after spinal cord injury. The resultant glucocor ticoid-induced immunosuppression, however, results in multiple complication s including sepsis, pneumonia, and wound infection, These complications cou ld be reduced by techniques that increase the spinal bioavailability of int ravenously administered methylprednisolone while simultaneously decreasing plasma bioavailability. This study aimed to characterize the spinal and pla sma bioavailability of methylprednisolone after intravenous and intrathecal administration and to identify barriers to the distribution of methylpredn isolone from plasma into spinal cord. Methods: The spinal and plasma pharmacokinetics of intravenous (30-mg/kg bo lus dose plus 5.4 mg . kg(-1). h(-1)) and intrathecal (1-mg/kg bolus dose p lus 1 mg . kg(-1). h(-1)) methylprednisolone infusions were compared in pig s, In addition, wild-type mice and P-glycoprotein knockout mice were used t o determine the role of P-glycoprotein in limiting spinal bioavailability o f methylprednisolone. Results: Despite the greater intravenous dose, concentrations of methylpred nisolone in pig spinal cord were far higher and plasma concentrations much lower after intrathecal administration. After intraperitoneal administratio n in the mouse, the concentrations of methylprednisolone in muscle were not different between mice expressing P-glycoprotein (2.39 +/- 1.79 mu g/g) an d those lacking P-glycoprotein (2.83 +/- 0.46 mu g/g). In contrast, methylp rednisolone was undetectable in spinal cords of wild-type mice, whereas con centrations in spinal cords of P-glycoprotein-deficient mice were similar t o those in skeletal muscle (2.83 +/- 0.27 mu g/g). Conclusions: These pig studies demonstrate that the spinal cord bioavailabi lity of methylprednisolone is poor after intravenous administration. The st udies In knockout mice suggest that this poor bioavailability results from P-glycoprotein-mediated exclusion of methylprednisolone from the spinal cor d.