Levels of Metrifonate and Dichlorvos in Plasma and Erythrocytes during Treatment of Schistosomiasis with Bilarcil®

Abstract

A method for the simultaneous quantitation of metrifonate (0,0‐dimethyl‐(1‐hydroxy‐2,2,2‐trichloroethyl)‐phosphonate) and dichlorvos (2,2‐dichlorovinyl dimethyl phosphate, DDVP) in human blood has been worked out. It is based upon multiple labelling of the compounds with deuterium and gas phase analysis using the mass spectrometer as a selective detector. The amount of DDVP in plasma is about 1% of the amount of metrifonate. In erythrocytes the corresponding amount of DDVP is 0.5% or less of metrifonate. Both compounds reach peak levels in blood within two hours after oral dosing and are detectable for at least eight hours. Cholinesterase activity in plasma reaches zero levels within 15 min. and remains inhibited for more than eight hours. Red blood cell cholinesterase is inhibited only 60‐80%. According to kinetic calculations, clearance of metrifonate occurs primarily via dichlorvos. If dichlorvos is the only active component, which in all likelihood it is, it's slow release may be important in the schistosomicidal effect. Clinical data in seven metrifonate treated patients revealed that mild vertigo subsiding in a few hours was the most common side effect.

Acetylcholinesterase of schistosoma mansoni—Functional correlates: Contributed in honor of Professor Hans Neurath's 90th birthday

“…It is, therefore, apparent that the cholinergic mechanisms are associated with neuromuscular function~Pax et al, 1996!. Indeed, schistosomal AChE is the target for several antiparasite drugs, including hycanthon, lucanthone, metrifonate, and phosphonium compounds~Bueding et Hillman et al, 1978;Nordgren et al, 1981;Levi-Schaffer et al, 1984a;Marshall, 1987!. In an early study in our laboratory, during the isolation of the tegumental membrane of schistosomula and analysis of its major components, we observed that AChE activity was highly enriched in the isolated external membrane, ca. 350-fold as compared to the entire worm~Levi-Schaffer et al, 1984b!.…”

Development and Clinical Application of Phosphorus-Containing Drugs

“…It selectively acts against the pyrophosphate binding site due to the structural mimic of anion pyrophosphate [ [105] , [106] ]. Antiparasitic drug metrifonate (Bilarcil/Memobay/ProMem®) ( 58 ) is an acetylcholinesterase inhibitor [ 107 ]. However, this drug was banned due to its high toxicity of metabolism dichlorvos in plants [ 108 ].…”

Therapeutic and Operational Profiles of Metrifonate and Praziquantel in Schistosoma haematobium Infection

“…Although metrifonate has been on the market for more than 20 years, its pharmacological characteristics have been determined only recently. The drug is quickly absorbed in all doses between 2.5 and 15 mg/kg with no significant inter-individual variation and with no evidence of dose dependence [50,63]. Peak plasma levels are reached within 2 h and the elimination half-life is 1.7 to 2.5 h [26,41,53].…”

“…Peak plasma levels are reached within 2 h and the elimination half-life is 1.7 to 2.5 h [26,41,53]. Cholinesterase activity in plasma reaches very low levels within 15 min and remains inhibited for at least five days independent of the dose [3,63]. Even two weeks after drug intake the activity of plasma cholinesterase remained below the normal value.…”

“…On the contrary, erythrocyte cholinesterase is suppressed in a dose-dependent fashion [50]. After a standard dose activity decreases to 60−80 % of the pre-treatment level [50,63]. In addition, erythrocyte cholinesterase activity, although depressed to a lesser extent needs a longer time to reach normal values again.…”