A pharmacokinetic study of neostigmine in man using gas chromatography-mass spectrometry

Summary

To permit rational evaluation of the empirical pharmacotherapy of myasthenia with cholinesterase inhibitors, a sensitive and selective method for the determination of neostigmine has been developed. Analysis is based on ion-pair extraction of neostigmine into methylene chloride and determination by gas chromatography-mass spectrometry (chemical ionization). As neostigmine was found to be metabolized in plasma in vitro, deuterated (d₆) neostigmine was immediately added to the plasma sample as the internal standard. The limit of quantitation of the method was about 1 ng/ml (∼ 3nmol/l). The kinetics following i. v. administration were studied in four patients, who received neostigmine 2.5–3.0 mg iv to antagonize pancurone administered during anaesthesia. Elimination was rapid with a half-life t_1/2 (β-slope) of 0.89±0.05 h (mean ± SE). The volume of distribution was 1.08±0.11 l/kg and plasma clearance was 0.84±0.04 l/kg/h. In three fasting myasthenic patients plasma concentrations of neostigmine were followed for 5 h after a single oral dose of 30 mg. Considerable interindividual differences in absorption were expressed in the peak concentrations, which occurred 1–2 h following drug ingestion. The bioavailability of neostigmine was estimated to be 1–2% of the ingested dose. Neostigmine concentration in plasma was found to differ considerably (up to forty-fold) between myasthenic patients on their ordinary dose-schedules of cholinesterase inhibitors.