CSF AND PLASMA PHARMACOKINETICS OF THE NMDA RECEPTOR ANTAGONIST CPP AFTER INTRATHECAL, EXTRADURAL AND IV ADMINISTRATION IN ANESTHETIZED PIGS

The N-methyl-D-aspartate (NMDA) receptor complex prays a central role in the modulation of neuronal information in the central nervous syste m. This study was designed to examine the pharmacokinetics of the NMDA antagonist 3-(2- carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) in plasma and cerebrospinal fluid (CSF) and rostral spread in the CSF after lumbar intrathecal, extradural and i.v. administration. Anaesth etized pigs were given a lumbar intrathecal, lumbar extradural or an i .v. injection of a mixture of [H-3]-labelled and unlabelled CPP. CSF w as sampled over 10 h through intrathecal catheters positioned at the L 1, T5 and C1 vertebral levels. Blood samples were obtained over the sa me period. Haemodynamic and arterial blood-gas variables and acid-base balance were monitored during the study. The area under the radioacti vity concentration-time curves showed a gradient between cervical and lumbar CSF radioactivity of about 1:2500 after intrathecal administrat ion and about 1:140 after extradural administration, indicating that o nly small fractions of lumbar administered CPP spread rostrally. About 2% of an extradurally administered dose was found in the CSF. After i .v. administration of [H-3]CPP, clearance was mean 122 (SEM 16) ml min (-1) and the CSF:serum radioactivity gradient was approximately 1:4. T he half-life of [H-3]CPP varied little (mean range 94-191 min) irrespe ctive of the route of administration or the level of sampling. Cervica l radioactivity after lumbar intrathecal administration probably resul ted from rostral transport via CSF bulk flow, whereas after extradural administration, systemic absorption and redistribution via the blood- brain barrier probably contributed. Renal excretion was the main route of systemic elimination. No effects on haemodynamics, arterial blood- gas tensions or acid-base balance could be correlated with intrathecal or extradural administration of CPP. The steep gradient between cervi cal and lumbar concentrations of [H-3] CPP suggests that it may be pos sible to administer CPP spinally at the lumbar level in pharmacologica lly active doses with little distribution to the supraspinal level.