Pharmacokinetics and pharmacodynamics of physostigmine in the rat after oral administration

The distribution, metabolism, and pharmacokinetics of physostigmine (Phy) and the time course of butyrylcholinesterase (BuChE) in plasma and cholinesterase (ChE) activity in brain and muscle and their relationship to Phy concentration were described after oral administration of 3H-Phy (650 micrograms kg-1) to rats. Physostigmine concentration vs time data was analyzed by nonlinear computer fitting program using one-compartment model. The absorption rate constant (ka) and elimination rate constant (ke) were found to be 0.1 +/- 0.07 min-1 and 0.036 +/- 0.024 min-1, respectively. Cpmax and tmax were 3.3 ng ml-1 and 16 min. The clearance (C1) was found to be 80.9 ml min-1kg-1. Half-life of Phy in brain, muscle, and liver were 33.4 min, 22.5, and 28 min, respectively. The bioavailability (F) was calculated to be 0.02 and the extraction ratio was found to be 0.98 indicating the 'first pass' effect. Butyrylcholinesterase activity in plasma was 76 per cent at 15 min and this activity did not change significantly up to 120 min. However, Phy concentration in plasma was very low; 2.89 ng ml-1 at 15 min and declined to 0.71 ng ml-1 at 90 min. Physostigmine concentration in brain peaked at 22 min to 2.85 +/- 1.09 ng g-1 and declined to 0.33 +/- 0.11 ng g-1 at 60 min. Cholinesterase activity in brain was 96 per cent, 82 per cent and 89 per cent at 10, 45, and 120 min, respectively. Physostigmine concentration in muscle was very low and the ChE activity in the muscle was 66.4 per cent of control at 45 min. The time course of Phy metabolism indicated that at 5 min most of the RA in the tissues was due to metabolites accounting for 94.6 per cent in plasma, 90 per cent in liver, 79.8 per cent in brain and 86.3 per cent in muscle. M1 appeared to be the major metabolite followed by eseroline. The results showed extremely low concentrations of Phy (200 times less in plasma and 350 times less in brain) after oral administration compared to our previous studies with the same dose after i.m. administration.