Pharmacology: There is increasing evidence that malfunctioning of glutamatergic neurotransmission, in particular at NMDA-receptors, contributes to both expression of symptoms and disease progression in neurodegenerative dementia. Memantine is a voltage-dependent, moderate-affinity uncompetitive NMDA-receptor antagonist. It modulates the effects of pathologically elevated tonic levels of glutamate that may lead to neuronal dysfunction.
Pharmacokinetics: Absorption: Memantine has an absolute bioavailability of approximately 100%. Tmax is between 3 and 8 hours. There is no indication that food influences the absorption of Memantine.
Distribution: Daily doses of 20 mg lead to steady-state plasma concentrations of Memantine ranging from 70-150 ng/mL (0.5-1 μmol) with large interindividual variations. When daily doses of 5-30 mg were administered, a mean cerebrospinal fluid (CSF)/serum ratio of 0.52 was calculated. The volume of distribution is around 10 L/kg. About 45% of Memantine is bound to plasma-proteins.
Biotransformation: In man, about 80% of the circulating Memantine-related material is present as the parent compound. Main human metabolites are N-3,5-dimethyl-gludantan, the isomeric mixture of 4- and 6-hydroxy-memantine, and 1-nitroso-3,5-dimethyl-adamantane. None of these metabolites exhibit NMDA-antagonistic activity. No cytochrome P 450 catalyzed metabolism has been detected in vitro.
Elimination: Memantine is eliminated in a monoexponential manner with a terminal t½ of 60-100 hours. In volunteers with normal kidney function, total clearance (Cltot) amounts to 170 ml/min/1.73 m2 and part of total renal clearance is achieved by tubular secretion.
Renal handling also involves tubular reabsorption, probably mediated by cation transport proteins. The renal elimination rate of Memantine under alkaline urine conditions may be reduced by a factor of 7-9. Alkalization of urine may result from drastic changes in diet, e.g. from a carnivore to a vegetarian diet, or from the massive ingestion of alkalizing gastric buffers.
Linearity: Studies in volunteers have demonstrated linear pharmacokinetics in the dose range of 10-40 mg.
Pharmacokinetic/pharmacodynamic relationship: At a dose of Memantine of 20 mg per day the CSF levels match the ki-value (ki = inhibition constant) of Memantine, which is 0.5 μmol in human frontal cortex.