Pharmacokinetics and pharmacodynamics of physostigmine after intravenous administration in beagle dogs

Abstract

The time course of physostigmine (Phy), its metabolites and activity of cholinesterase (ChE) in plasma were studied after intravenous bolus administration of [ 3H]Phy (100 μg/kg) to beagle dogs. The maximal inhibition of ChE (78%) in plasma at 2 min correlated with the largest concentration of physostigmine (124 ng/ml). The concentration of physostigmine decreased by 88% to 16 ng/ml at 45 min when the activity of ChE was still 59% inhibited. Acetylcholinesterase activity in four regions of the brain (medulla, striatum, cerebellum and cortex) was not significantly different from controls at 70 ± 5 min after administration of physostigmine. Concentrations of physostigmine and its metabolites determined by HPLC were not significantly different in different regions. In plasma, physostigmine was found, together with eseroline and two other metabolites M 1 and M 2. At 45 min, only 18% of total radioactivity was due to physostigmine and 52% was due to the major metabolite M 1. On the contrary, in regions of the brain, metabolite M 1 represented only 1.9–3.37% of total radioactivity at 70 ± 5 min. Pharmacokinetic parameters, obtained in the dog, were compared to previously published data in rat and man. The elimination half-life (β) was 30.7 min in the dog as compared to 15 min in rat and and 21.7 min in man. The V d ml/kg was higher than total body water volume in all three species: dog (1832), rat (1352) and man (664), indicating sequestration of the drug in body compartments. Clearance (ml/min/kg) was found to be 41.2 in dog, which compares to 62 in rat and 22 in man. The differences between species in these pharmacokinetic parameters suggest an interspecies variation. It is felt the pharmacokinetic data and the inhibition curves for ChE, obtained in this study, will be of value in determining dose regimens for the clinical use of physostigmine.