Physiological pharmacokinetic and pharmacodynamic model of physostigmine in the rat.
A physiological model for physostigmine disposition was developed in the rat which incorporated anatomical, physiological, and biochemical parameters, i.e. tissue volume, plasma flow rates, drug metabolism, and tissue-to-plasma partition coefficients. Predicted concentrations of physostigmine in different tissue compartments were consistent with the experimental observations in the rat following an iv dose. Part of this study also compared the time course changes in measured effect, as percentage change in cholinesterase activity in brain, and related these changes to the plasma or brain drug level in either a combined pharmacokinetic-pharmacodynamic (plasma physostigmine-effect relationship) or a dynamic model (brain physostigmine-effect relationship). Fitting the time course of the effect in a pharmacokinetic-pharmacodynamic model required an effect compartment with the equilibration rate constant between it and the plasma compartment. Both models help to understand whether the cholinesterase activity is homogeneous or heterogenous in the brain.
Somani
S M
SM
Department of Pharmacology, Southern Illinois University School of Medicine, Springfield 62794-9230.
Gupta
S K
SK
Khalique
A
A
Unni
L K
LK
D000818:Animals; D001921:Brain / Q000201:enzymology; D002800:Cholinesterase Inhibitors; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D010830:Physostigmine / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D002800:Cholinesterase Inhibitors; D010830:Physostigmine