Cyclosporine-A-mediated inhibition of p-glycoprotein increases methylprednisolone entry into the central nervous system.
METHODS
Prospective, randomized, pharmacokinetic study.


OBJECTIVE
To determine if cyclosporine-A-mediated inhibition of p-glycoprotein would increase methylprednisolone entry into the central nervous system thereby permitting a reduction in the systemic methylprednisolone dose.


METHODS
Department of Anesthesiology, University of Washington, Seattle, USA.


METHODS
Microdialysis probes were used to obtain cerebrospinal fluid and gluteal muscle extracellular fluid samples for measurement of methylprednisolone concentration in pigs. At time zero, a methylprednisolone bolus was given and an infusion started. At 210 min, after reaching a stable methylprednisolone concentration, a cyclosporine-A bolus was given (either 10 or 30 mg/kg) and microdialysis samples collected until 420 min. Plasma samples were collected at 10, 30 min and then every 30 min until the study's end.


RESULTS
Cyclosporine-A bolus produced a dose-dependant increase in methylprednisolone concentration in plasma, muscle and cerebrospinal fluid. Importantly, the magnitude of the increase in cerebrospinal fluid was significantly greater than the increase in plasma and muscle.


CONCLUSIONS
The relatively greater increase in cerebrospinal fluid concentrations of methylprednisolone is consistent with increased penetration of the blood-brain barrier secondary to cyclosporine-mediated p-glycoprotein inhibition. Theoretically, increased methylprednisolone entry into the central nervous system should allow a reduction in the systemic methylprednisolone dose and a consequent decrease in glucocorticoid-mediated side effects.
Bernards
C M
CM
Department of Anesthesiology, Virginia Mason Medical Center, University of Washington, Seattle, WA 98101-2756, USA.
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D005260:Female; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008775:Methylprednisolone / Q000008:administration & dosage / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics*; D018482:Muscle, Skeletal / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D011446:Prospective Studies; D011897:Random Allocation; D013552:Swine; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004338:Drug Combinations; D018696:Neuroprotective Agents; D016572:Cyclosporine; D008775:Methylprednisolone