Nonlinear model for acetazolamide.

Abstract

Intravenous bolus injections of 14C-labeled acetazolamide were made in rabbits. Plasma, urine, and washed red blood cell concentrations were measured, the latter indicating bound drug. AUTOAN and NONLIN were used to fit the plasma data to a linear two-compartment model. However, utilization of the urine and red blood cell data suggested that a nonlinear model was more appropriate. The developed nonlinear system uses a one-compartment model with two tissue-binding parameters. The system simultaneously fits three equations describing drug in the plasma, in the body, and bound to red blood cells, Six parameters were estimated. The initial plasma concentration and the maximum amount bound to tissue protein (minus red blood cell protein) correlated with dose. The dissociation constant from this protein fraction suggested that it is composed mainly of the enzyme, carbonic anhydrase. The dissociation constant for the red blood cell fraction suggested that the drug binds to other protein in addition to carbonic anhydrase. The elimination constants were quite similar, indicating little variation from one animal to another. Utilization of the concepts of site and mechanism of action in this model should be of considerable help in relating drug concentration to pharmacological resonse.