Brain penetration and in vivo recovery of NMDA receptor antagonists amantadine and memantine: a quantitative microdialysis study.
OBJECTIVE
To determine free brain concentrations of the clinically used uncompetitive NMDA antagonists memantine and amantadine using microdialysis corrected for in vivo recovery in relations to serum, CSF and brain tissue levels and their in vitro potency at NMDA receptors.


METHODS
Microdialysis corrected for in vivo recovery was used to determine brain ECF concentrations after steady-state administration of either memantine or amantadine. Additionally CSF, serum, and brain tissue were analyzed.


RESULTS
Following 7 days of infusion of memantine or amantadine (20 and 100 mg/kg/day respectively) whole brain concentrations were 44-and 16-fold higher than free concentrations in serum respectively. The free brain ECF concentration of memantine (0.83 +/- 0.05 microM) was comparable to free serum and CSF concentrations. In case of amantadine, it was lower. A higher in vivo than in vitro recovery was found for memantine.


CONCLUSIONS
At clinically relevant doses memantine reaches a brain ECF concentration in range of its affinity for the NMDA receptor and close to its free serum concentration. This is not the case for amantadine and different mechanisms of action may be operational.
Hesselink
M B
MB
Department of Pharmacological Research, Merz + Co., Frankfurt/Main, Germany.
De Boer
B G
BG
Breimer
D D
DD
Danysz
W
W
D000547:Amantadine / Q000032:analysis / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D015259:Dopamine Agents / Q000032:analysis / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D018691:Excitatory Amino Acid Antagonists / Q000032:analysis / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D005110:Extracellular Space / Q000737:chemistry; D008297:Male; D008559:Memantine / Q000032:analysis / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D015259:Dopamine Agents; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D000547:Amantadine; D008559:Memantine