T. N. Calvey, N. Williams, K. Chan
Dec 1, 1981
Citations
0
Influential Citations
1
Citations
Quality indicators
Journal
Annals of the New York Academy of Sciences
Abstract
Although intramuscular neostigmine methylsulfate is frequently used during diagnosis or initial therapy in patients with myasthenia gravis, little is known of its metabolism and excretion in these circumstances. The kinetics and disposition of neostigmine methylsulfate ( 1 .O-2.0 mg intramuscularly) was therefore studied in eight myasthenic patients who had a history of voluntary muscle fatiguability for a period of two months to two years. In most subjects, characteristic electromyographic changes were observed and a positive response to edrophonium chloride (“Tensilon”) was obtained. None of the patients were currently taking other compounds or were on anticholinesterase drugs. Studies of the plasma concentration of neostigmine were carried out in five myasthenic patients after intramuscular injection of the drug (2.0 mg). In two subjects, neostigmine was detected in plasma within 15 min. In all five patients, the plasma concentration invariably declined in a monoexponential manner from 21 k 2 ng/ml (mean f S.E.M.) to 9 k 1 ng/ml (mean +S.E.M.) between 30 and 120 min. Small concentrations of neostigmine (5-7 ng/ml) were present in plasma at 150 min in three subjects; in one instance, the drug was stilI detectable at 180 rnin. None of the quaternary amine could be detected in plasma in any of the five patients at 240 min. In other myasthenic patients, the elimination of the drug and its metabolites in urine was studied after intramuscular administration of 14C-neostigmine (1.0 or 2.0 mg neostigmine methylsulfate containing 1.5 pCi of I4C-neostigmine). Unchanged neostigmine and its principal identified metabolites (i.e., 3-hydroxyphenyltrimethylammonium and its 3-oxyglucuronide) were isolated from urine, and identified by both ion exchange and paper chromatography. Approximately 80% of the drug was excreted in urine, either as unchanged neostigmine or its metabolites, within 24 hours. At this time, roughly 50% of the dose was eliminated as the unchanged drug, 15% as 3-hydroxyphenyltrimethylammonium, and 15% as other unidentified metabolites. The decline in the concentration of neostigmine in plasma and urine was interpreted in terms of a one compartment open pharmacokinetic model. Estimates of the plasma half-life of neostigmine varied from 51.1-90.5 min,