Brain penetration and in vivo recovery of NMDA receptor antagonists amantadine and memantine: a quantitative microdialysis study

Pharm Res. 1999 May;16(5):637-42. doi: 10.1023/a:1018856020583.


Purpose: 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.

MeSH terms

  • Amantadine / analysis
  • Amantadine / cerebrospinal fluid
  • Amantadine / pharmacokinetics*
  • Animals
  • Biological Transport / drug effects
  • Brain Chemistry / drug effects*
  • Dopamine Agents / analysis
  • Dopamine Agents / chemical synthesis
  • Dopamine Agents / pharmacokinetics*
  • Excitatory Amino Acid Antagonists / analysis
  • Excitatory Amino Acid Antagonists / cerebrospinal fluid
  • Excitatory Amino Acid Antagonists / pharmacokinetics*
  • Extracellular Space / chemistry
  • Male
  • Memantine / analysis
  • Memantine / cerebrospinal fluid
  • Memantine / pharmacokinetics*
  • Microdialysis
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*


  • Dopamine Agents
  • Excitatory Amino Acid Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • Amantadine
  • Memantine