THE PHARMACOLOGICAL BASIS FOR METRIFONATES FAVORABLE TOLERABILITY IN THE TREATMENT OF ALZHEIMERS-DISEASE

Metrifonate, through its pharmacologically active metabolite 2,2-dichl orovinyl dimethylphosphate (DDVP), is a long-acting cholinesterase inh ibitor for the symptomatic treatment of mild-to-moderate Alzheimer's d isease. 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. greater than or equal to 70%, without the need for dose escalation. This is a consequence of the low rate o f fluctuation of enzyme activity during therapy with metrifonate. This , in turn, is due to the protracted hydrolytic transformation of metri fonate into DDVP, the resulting smooth onset of cholinesterase inhibit ion, and the subsequent long duration of action which far outlasts the presence of the active drug in the body. Both metrifonate and DDVP ar e rapidly metabolized and eliminated from the body. Further, their met abolism does not involve the cytochrome P450 system and both compounds show low plasma protein binding. These pharmacokinetic features accou nt, at least in part, for the favourable safety and tolerability profi le of metrifonate as they suggest a minimal risk of drug-drug interact ions with other likely co-medications in the long-term therapy of Alzh eimer patients.