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Brain Penetration and In Vivo Recovery of NMDA Receptor Antagonists Amantadine and Memantine: A Quantitative Microdialysis Study

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Abstract

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 μM) 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.

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Authors and Affiliations

  1. Department of Pharmacological Research, Merz + Co., Eckenheimer Landstrasse 100, 60, 318, Frankfurt/Main, Germany

    Mayke B. Hesselink & Wojciech Danysz

  2. Department Pharmacology, Leiden/Amsterdam Center for Drug Research, Einsteinweg 55, 2300 RA, Leiden, The Netherlands

    Mayke B. Hesselink, Bert G. De Boer & Douwe D. Breimer

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  1. Mayke B. Hesselink
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  2. Bert G. De Boer
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  3. Douwe D. Breimer
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  4. Wojciech Danysz
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Correspondence to Wojciech Danysz.

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Hesselink, M.B., De Boer, B.G., Breimer, D.D. et al. Brain Penetration and In Vivo Recovery of NMDA Receptor Antagonists Amantadine and Memantine: A Quantitative Microdialysis Study. Pharm Res 16, 637–642 (1999). https://doi.org/10.1023/A:1018856020583

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