THERAPEUTIC BRAIN CONCENTRATION OF THE NMDA RECEPTOR ANTAGONIST AMANTADINE

Amantadine (1-amino-adamantane) is clinically used for the management of Parkinson's disease and drug-induced extrapyramidal symptoms. It ha s previously been shown that amantadine is a low-affinity uncompetitiv e N-methyl-D-aspartate (NMDA) receptor antagonist with rapid blocking and unblocking channel kinetics (K-i-value at the PCP binding site = 1 0 mu M). The aim of the present studies was to estimate concentrations of amantadine in the central nervous system under therapeutic conditi ons. In homogenates of postmortem human brain tissue the amantadine co ncentration appeared to be homogeneously distributed over a wide range of brain areas. Amantadine concentration increased with duration of t reatment and decreased with drug-free time. When the duration of treat ment was greater than or equal to 10 days and drug-free time less than or equal to 3 days, mean amantadine concentrations in postmortem brai n tissue ranged from 48.2 to 386 mu M. In contrast to brain tissue, am antadine concentration in cerebrospinal fluid (CSF) and serum was in t he low micromolar range (< 17 mu M). CSF and serum total values were h ighly correlated to each other and were always lower in CSF. The mean CSF/serum ratio for total amantadine was 0.76. To further estimate the extracellular concentration, amantadine was determined in microdialys ates in the rat striatum. At behaviorally active doses, amantadine con centration in striatal microdialysates ranged between 6 and 21 mu M. T hese results indicate that extracellular concentrations of amantadine (CSF and serum values in patients, striatal microdialysates in the rat ) are in the range of its K-i-value at the PCP binding site. Amantadin e concentrations in brain tissue are much higher, probably due to intr alysosomal accumulation.