EVIDENCE FOR LYSOSOMOTROPISM OF MEMANTINE IN CULTURED HUMAN-CELLS - CELLULAR KINETICS AND EFFECTS OF MEMANTINE ON PHOSPHOLIPID CONTENT AND COMPOSITION, MEMBRANE FLUIDITY AND BETA-ADRENERGIC TRANSMISSION

Memantine, an amantadine derivative, is therapeutically used for the t reatment of various neurological and psychiatric disorders such as Par kinson's disease, spasticity, and dementia. Pharmacokinetics of memant ine and its effects on phospholipid content and composition, on membra ne properties and functions such as fluidity and beta-adrenergic trans mission were studied in cultured human fibroblasts and macrophages. Th e kinetic behaviour of memantine was characteristic for a lysosomotrop ic drug. Fibroblasts exposed to C-14-memantine in the muM range accumu lated the drug up to 200 fold above initial medium concentrations. Lys osomal drug storage was proven by indirect evidence and by analyses of subcellular fractions. Repetitive exposure to memantine resulted in a cumulative uptake. While memantine uptake after single exposure was f ully reversible, the rate and extent of release of chronically accumul ated drug was reduced but could be enhanced by the addition of unlabel led memantine or ammonium chloride to the medium. Chronic, but not sin gle, exposure to memantine above 10 muM resulted in a concentration de pendent phospholipid accumulation and in a shift in the phospholipid c omposition. There was an overproportionate increase in phosphatidylino sitol at the expense of phosphatidylserine and sphingomyelin. Chronic exposure of cultured cells to memantine increased fluidity in the supe rficial layers of the plasma membrane and reduced the isoproterenol-st imulated cAMP-response without affecting beta-adrenoceptor density. Al l these findings were compatible with the kinetic behaviour and the ef fectiveness expected of a weak lysosomotropic drug.