Schmidt B H, Heinig R
Bayer CNS Research, Köln, Germany.
Dement Geriatr Cogn Disord. 1998;9 Suppl 2:15-9. doi: 10.1159/000051194.
Metrifonate, through its pharmacologically active metabolite 2,2-dichlorovinyl dimethylphosphate (DDVP), is a long-acting cholinesterase inhibitor for the symptomatic treatment of mild-to-moderate Alzheimer's disease. Clinical studies with Alzheimer patients have demonstrated the favourable safety and tolerability profile of this drug. Metrifonate, at therapeutic doses for Alzheimer's disease, achieves high levels of cholinesterase inhibition, i.e. > or =70%, without the need for dose escalation. This is a consequence of the low rate of fluctuation of enzyme activity during therapy with metrifonate. This, in turn, is due to the protracted hydrolytic transformation of metrifonate into DDVP, the resulting smooth onset of cholinesterase inhibition, and the subsequent long duration of action which far outlasts the presence of the active drug in the body. Both metrifonate and DDVP are rapidly metabolized and eliminated from the body. Further, their metabolism does not involve the cytochrome P450 system and both compounds show low plasma protein binding. These pharmacokinetic features account, at least in part, for the favourable safety and tolerability profile of metrifonate as they suggest a minimal risk of drug-drug interactions with other likely co-medications in the long-term therapy of Alzheimer patients.
敌百虫通过其药理活性代谢物2,2-二氯乙烯基二甲基磷酸酯（敌敌畏），是一种长效胆碱酯酶抑制剂，用于对症治疗轻度至中度阿尔茨海默病。对阿尔茨海默病患者的临床研究表明了该药物良好的安全性和耐受性。在用于阿尔茨海默病的治疗剂量下，敌百虫可实现高水平的胆碱酯酶抑制，即≥70%，而无需增加剂量。这是由于在敌百虫治疗期间酶活性波动率较低。反过来，这又归因于敌百虫向敌敌畏的持久水解转化、胆碱酯酶抑制作用的平稳起效以及随后远远超过体内活性药物存在时间的长效作用。敌百虫和敌敌畏均迅速代谢并从体内消除。此外，它们的代谢不涉及细胞色素P450系统，且两种化合物的血浆蛋白结合率都很低。这些药代动力学特征至少部分解释了敌百虫良好的安全性和耐受性，因为它们表明在阿尔茨海默病患者的长期治疗中，与其他可能的合用药物发生药物相互作用的风险极小。
