Pharmacokinetics and pharmacodynamics of physostigmine in the rat after intravenous administration

The time course of physostigmine (Phy) and metabolites in plasma, brain, and muscle, the inhibition of butyrylcholinesterase (BuChE) in plasma, and cholinesterase (ChE) activity in brain and muscle were studied in rat after iv bolus administration of 3H-Phy (100 micrograms/kg). The semilogarithmic plot of plasma Phy concentration versus time indicates a biphasic decline. These data were analyzed by nonlinear computer fitting program (PC-NONLIN) using a two-compartment open model with bolus input and first order elimination. The pharmacokinetic constants A, B, alpha, beta, AUC, K10 half-life, alpha-half-life, beta-half-life, K10, K12, and K21 were obtained. The alpha-half-life and the beta-half-life were 1.31 and 15.01 min, respectively. The apparent volume of distribution was found to be 270 ml. The clearance was 12.43 ml min-1. The half-life of Phy in brain was 11 min. The brain to plasma ratio (1.69) peaked at 15 min. Phy is metabolized to eseroline and three other metabolites, M1, M2, and M3. The distribution studies showed that the radioactivity per g of tissue was highest in kidney and liver, whereas the percentage of the administered dose in terms of radioactivity was maximum in muscle followed by liver. The maximum inhibition of BuChE (52%) correlates with the highest Phy concentration (84.6 ng/ml) in plasma at 2 min and 70% of the enzymic activity recovered by 45 min. The maximum inhibition of ChE (63%) in the brain correlates with the highest Phy concentration (128 ng/g) at 3 min, and 85% of the enzymic activity was recovered within an hour.(ABSTRACT TRUNCATED AT 250 WORDS)