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

Purpose: To determine free brain concentrations of the clinically used unco mpetitive NMDA antagonists memantine and amantadine using microdialysis cor rected for in vivo recovery in relations to serum, CSF and brain tissue lev els 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 meman tine or amantadine. Additionally CSF, serum, and brain tissue were analyzed . Results: Following 7 days of infusion of memantine or amantadine (20 and 10 0 mg/kg/day respectively) whole brain concentrations were 44-and 16-fold hi gher than free concentrations in serum respectively. The free brain ECF con centration of memantine (0.83 +/- 0.05 mu M) was comparable to free serum a nd CSF concentrations. In case of amantadine, it was lower. A higher in viv o than in vitro recovery was found for memantine. Conclusions: At clinically relevant doses memantine reaches a brain ECF con centration 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.