T. N. Calvey, D. Back
Aug 1, 1971
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Journal of Pharmacy and Pharmacology
Abstract
Although edrophonium chloride (ethyldimethyl(3-hydroxyphenyl)ammonium chloride) is occasionally used for diagnostic purposes in man, little is known of its metabolism and excretion. In general, chemically reversible anticholinesterase drugs have rapid and evanescent effects (Randall, 1950) ; in these conditions, detoxication may have little or no influence on pharmacological action. Indeed, it is commonly assumed that most quaternary amines are not metabolized, since the lipophilic endoplasmic reticulum may restrict the penetration and limit the metabolism of polar compounds (Gaudette & Brodie, 1959). These limitations do not necessarily apply to all polar drugs (Maze1 & Henderson, 1965) or low molecular weight quaternary compounds (Somani, Wright & Calvey, 1970). For these reasons, and since no previous studies of the metabolism of edrophonium have been reported, we have studied the excretion of this drug and its metabolic products in bile. The common bile duct of Wistar rats of either sex was cannulated under urethane anaesthesia, and bile was collected at hourly intervals after intravenous injection of [14C]edrophonium chloride (2.0 pmol/kg) in saline. Specimens were assayed for radioactivity by liquid scintillation spectrometry, and [14C]edrophonium and its metabolites were detected by paper and thin-layer chromatography in at least five different solvent systems. Conjugates of edrophonium in bile were identified by incubation with 8-glucuronidase ; control specimens were incubated with the enzyme in the presence of the specific inhibitor glucaro-(1+4)-lactone. In 24 experiments, 4.7 f 2.3 % (mean & s.d.) of the dose of [14C]edrophonium was excreted in bile in 6 h. The only significant metabolite identified was a 3-oxyglucuronide conjugate of edrophonium { [14C]ethyldimethyl(3-oxyphenyl)ammomum glucuronide}. Approximately 89 % of the radioactivity in bile was present as this metabolite 1 h after administration of the drug (Table 1); some 10% was excreted as ['TIedrophonium. Only small amounts of the unchanged drug were identified 2-6 h after injection. Thus, the presence of unchanged edrophonium in bile may represent diffusion of the drug from periductular plasma downstream from the biliary canaliculus. The trimethyl analogue of edrophonium (trimophonium) is partly demethylated before biliary excretion (Somani & others, 1970). In the present experiments, approximately 1 % of the total radioactivity in bile was eliminated as an unidentified metabolite ; it is possible that this substance represents a dealkylated conjugate of edrophonium.