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

Background: High-dose intravenously administered methylprednisolone has been shown to improve outcome after spinal cord injury. The resultant glucocorticoid-induced immunosuppression, however, results in multiple complications including sepsis, pneumonia, and wound infection, These complications could be reduced by techniques that increase the spinal bioavailability of intravenously administered methylprednisolone while simultaneously decreasing plasma bioavailability. This study aimed to characterize the spinal and plasma bioavailability of methylprednisolone after intravenous and intrathecal administration and to identify barriers to the distribution of methylprednisolone from plasma into spinal cord. Methods: The spinal and plasma pharmacokinetics of intravenous (30-mg/kg bolus dose plus 5.4 mg . kg(-1). h(-1)) and intrathecal (1-mg/kg bolus dose plus 1 mg . kg(-1). h(-1)) methylprednisolone infusions were compared in pigs, In addition, wild-type mice and P-glycoprotein knockout mice were used to determine the role of P-glycoprotein in limiting spinal bioavailability of methylprednisolone. Results: Despite the greater intravenous dose, concentrations of methylprednisolone in pig spinal cord were far higher and plasma concentrations much lower after intrathecal administration. After intraperitoneal administration in the mouse, the concentrations of methylprednisolone in muscle were not different between mice expressing P-glycoprotein (2.39 +/- 1.79 mu g/g) and those lacking P-glycoprotein (2.83 +/- 0.46 mu g/g). In contrast, methylprednisolone was undetectable in spinal cords of wild-type mice, whereas concentrations in spinal cords of P-glycoprotein-deficient mice were similar to those in skeletal muscle (2.83 +/- 0.27 mu g/g). Conclusions: These pig studies demonstrate that the spinal cord bioavailability of methylprednisolone is poor after intravenous administration. The studies In knockout mice suggest that this poor bioavailability results from P-glycoprotein-mediated exclusion of methylprednisolone from the spinal cord.