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Hepatic and muscle clearance of physostigmine in the rat.

Physostigmine (Phy) was rapidly metabolized by rat liver after iv (100 micrograms/kg) or im (650 micrograms/kg) administration. The half-life of Phy in liver after iv and im administration was found to be 24 and 26 min, respectively, indicating that Phy does not show dose-dependent kinetics. The half-life of Phy in muscle after iv administration was 20 min. The extraction ratio and the clearance from the liver and muscle were calculated. Hepatic clearance ws found to be 23.08 ml/min/kg (34.90% of systemic clearance) and the intrinsic clearance from the liver was 83.73 ml/min/kg. The percentage dose was found to be maximal in the muscle and the clearance was about 5.2 ml/min/kg. It appears that 30-40% of radioactivity was bound to the liver precipitate and could not be washed off by 10% trichloroacetic acid or organic solvents. Phy and the metabolites, eseroline (Es), M1, M2, and M3 were separated by HPLC, collecting the radioactive fractions. The time course of radioactivity per gram of liver after iv dosing (100 micrograms/kg), showed the major metabolite to be M1, followed by M2 and Es, whereas after im dosing (650 micrograms/kg), Es was present in larger amounts than were other metabolites. Phy appeared to be slowly metabolized in the muscle after iv administration. Liver played a major role in the metabolism of Phy.