CSF and plasma pharmacokinetics of the NMDA receptor antagonist CPP after intrathecal, extradural and i.v. administration in anaesthetized pigs.

The N-methyl-D-aspartate (NMDA) receptor complex plays a central role in the modulation of neuronal information in the central nervous system. 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. Anaesthetized pigs were given a lumbar intrathecal, lumbar extradural or an i.v. injection of a mixture of [3H]-labelled and unlabelled CPP. CSF was sampled over 10 h through intrathecal catheters positioned at the L1, T5 and C1 vertebral levels. Blood samples were obtained over the same period. Haemodynamic and arterial blood-gas variables and acid-base balance were monitored during the study. The area under the radioactivity concentration-time curves showed a gradient between cervical and lumbar CSF radioactivity of about 1:2500 after intrathecal administration and about 1:140 after extradural administration, indicating that only 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 [3H]CPP, clearance was mean 122 (SEM 16) ml min-1 and the CSF: serum radioactivity gradient was approximately 1:4. The half-life of [3H]CPP varied little (mean range 94-191 min) irrespective of the route of administration or the level of sampling. Cervical radioactivity after lumbar intrathecal administration probably resulted from rostral transport via CSF bulk flow, whereas after extradural administration, systemic absorption and redistribution via the blood-brain barrier probably contributed.(ABSTRACT TRUNCATED AT 250 WORDS)