Honegger U E, Quack G, Wiesmann U N
Department of Pharmacology, University of Bern, Switzerland.
Pharmacol Toxicol. 1993 Oct;73(4):202-8. doi: 10.1111/j.1600-0773.1993.tb01564.x.
Memantine, an amantadine derivative, is therapeutically used for the treatment of various neurological and psychiatric disorders such as Parkinson's disease, spasticity, and dementia. Pharmacokinetics of memantine and its effects on phospholipid content and composition, on membrane properties and functions such as fluidity and beta-adrenergic transmission were studied in cultured human fibroblasts and macrophages. The kinetic behaviour of memantine was characteristic for a lysosomotropic drug. Fibroblasts exposed to 14C-memantine in the microM range accumulated the drug up to 200 fold above initial medium concentrations. Lysosomal 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 fully reversible, the rate and extent of release of chronically accumulated drug was reduced but could be enhanced by the addition of unlabelled memantine or ammonium chloride to the medium. Chronic, but not single, exposure to memantine above 10 microM resulted in a concentration dependent phospholipid accumulation and in a shift in the phospholipid composition. There was an overproportionate increase in phosphatidylinositol at the expense of phosphatidylserine and sphingomyelin. Chronic exposure of cultured cells to memantine increased fluidity in the superficial layers of the plasma membrane and reduced the isoproterenol-stimulated cAMP-response without affecting beta-adrenoceptor density. All these findings were compatible with the kinetic behaviour and the effectiveness expected of a weak lysosomotropic drug.
美金刚是一种金刚烷胺衍生物，在治疗上用于治疗各种神经和精神疾病，如帕金森病、痉挛和痴呆。在培养的人成纤维细胞和巨噬细胞中研究了美金刚的药代动力学及其对磷脂含量和组成、对膜特性和功能（如流动性和β-肾上腺素能传递）的影响。美金刚的动力学行为是溶酶体趋向性药物的特征。暴露于微摩尔范围内的14C-美金刚的成纤维细胞积累的药物浓度比初始培养基浓度高出200倍。通过间接证据和亚细胞组分分析证明了溶酶体药物储存。重复暴露于美金刚导致累积摄取。单次暴露后美金刚的摄取是完全可逆的，而长期积累药物的释放速率和程度降低，但可通过向培养基中添加未标记的美金刚或氯化铵来提高。长期（而非单次）暴露于高于10微摩尔的美金刚会导致浓度依赖性磷脂积累和磷脂组成的改变。以磷脂酰丝氨酸和鞘磷脂为代价，磷脂酰肌醇有过度增加。培养细胞长期暴露于美金刚会增加质膜表层的流动性，并降低异丙肾上腺素刺激的cAMP反应，而不影响β-肾上腺素能受体密度。所有这些发现与弱溶酶体趋向性药物的动力学行为和预期效果一致。
