Role of concentration-dependent plasma protein binding in disopyramide disposition

Abstract

Plasma disopyramide concentration-time data and plasma protein binding measurements were obtained in 12 patients requiring disopyramide for suppression of their cardiac arrhythmias. The fraction of disopyramide unbound to plasma proteins varies from approximately 0.19 to 0.46 over the therapeutic range of total plasma concentrations (2–8 mg/liter). Data from single and multiple intravenous doses were analyzed using two models based on the hypothesis either that clearance is independent of the total disopyramide plasma concentration (total clearance model) or that clearance is independent of the concentration of disopyramide unbound to plasma proteins (free clearance model). This analysis indicates that only the free clearance model satisfactorily describes the data as a linear system. Using the free clearance model and data obtained from single doses, multiple intravenous infusions were designed for each patient which would rapidly attain and maintain predetermined plasma disopyramide concentrations. The calculated and observed disopyramide concentrations were in close agreement. In the 12 patients studied, at any given total disopyramide plasma concentration, there was an approximately twofold range in the fraction of disopyramide unbound to plasma proteins. Mean plasma protein binding data are therefore of little value in a given patient for predicting free disopyramide concentrations from measurements of total disopyramide concentration. Difficulties in the clinical management of patients receiving disopyramide, resulting from the nonlinear disposition of the usually measured total disopyramide concentrations, are discussed.