ACTIVE-TRANSPORT OF METHOTREXATE FROM CEREBROSPINAL-FLUID IN HUMANS

Abstract

The CSF efflux kinetics of methotrexate (MTX) were studied in 3 patients with indwelling Ommaya reservoirs. A small dose of MTX was injected intraventricularly several hours after the start of a high-dose continuous i.v. infusion of MTX. The CSF antifolate concentration returned to the preinjection level before the end of the i.v. infusion. The efflux of MTX from CSF in humans is independent of plasma drug concentrations. Efflux kinetics were further characterized in 1 patient. Serially obtained CSF samples after intraventricular injections demonstrated a biphasic disappearance curve with .alpha.- and .beta.-phase half-disappearance times of 1.7 and 6.6 h, respectively. Prolongation of the .beta.-phase half-time was associated with oral acetazolamide medication and with increased intracranial pressure, indicating that inhibition of CSF production slows MTX clearance. CSF MTX concentration, however, declined more rapidly than that of simultaneously administered diethylenetriaminepentaacetic acid, an extracellular marker substance excreted by bulk flow, indicating that bulk flow excretion alone is insufficient to account for MTX efflux from human CSF. Evidence that there is an active transport component was provided by probenecid pretreatment which also prolonged the CSF MTX half-life. Passive and active mechanisms govern MTX efflux from the CSF in humans. [Effective chemotherapeutic treatment of neoplastic meningeal disease is dependent upon the achievement of sufficient drug concentrations for an appropriate period of time.].