Spinal cord injuries causing permanent neurologic damage affect approximately 280,000 Americans. The only currently available therapy shown to reduce the severity of neurologic damage is massive intravenous doses of a glucocorticoid (methylprednisolone) administered during the first 3-48 hrs after injury. Unfortunately, the benefit of methylprednisolone therapy in terms of neurologic recovery is relatively small and the deleterious side effects of huge, immune-suppressive glucocorticoid doses are significant (e.g., sepsis, pneumonia). In fact, there is reason to believe that the deleterious systemic side-effects of high dose methylprednisolone therapy may actually ameliorate some of the potential neurologic benefit. Thus, developing drug delivery strategies that increase the bioavailability of methylprednisolone in the spinal cord and therefore allow a parallel reduction in the required systemic dose may significantly improve outcome. To achieve this goal of improved therapeutic index requires a thorough understanding of methylprednisolone's pharmacokinetics. Unfortunately this information is not currently available. In addition, it is essential to understand why the bioavailability of methylprednisolone in the spinal cord is so poor after intravenous methylprednisolone administration. To achieve these goals we propose the following aims: 1. To thoroughly define methylprednisolone's compartmental pharmacokinetics (spinal cord, plasma, cerebrospinal fluid) following intrathecal and intravenous administration. 2. To identify the role of p-glycoprotein in limiting methylprednisolone penetration of the blood-spinal cord barrier. 3. To identify p-glycoprotein inhibitors that increase the spinal cord bioavailability of intravenously and intrathecally administered methylprednisolone. 4. To determine whether increased spinal cord bioavailability of methylprednisolone decreases secondary damage following spinal cord injury.
