The pharmacokinetic and pharmacodynamic effects of varying the free fraction of disopyramide.

We have evaluated the influence of several factors on the binding of disopyramide to protein in human serum using a new ultrafiltration system and the enzyme multiplied immunoassay technique (EMIT) for disopyramide immunoassay. From these studies and those of other investigators, we conclude that the most significant in vivo factors influencing disopyramide binding in human serum are total disopyramide concentration, the concentration of alpha 1-acid glycoprotein, and the concentration of mono-N-dealkyldisopyramide. Significant variation in binding occurs in patients whose total disopyramide concentration is within the therapeutic range. The proportion of free disopyramide ranged from 16% to 54% in the sera of 50 cardiac patients whose total disopyramide concentration ranged from 0.5 to 5.8 mcg/ml. Since there is so much variation in the proportion of disopyramide that is free, and since it is the unbound form of the drug that is pharmacologically active, it is likely in patients whose arrhythmia responds to disopyramide therapy that unbound drug concentration will be a better indicator of drug efficacy and toxicity than will be total drug concentration. To test this hypothesis, we are investigating the relationship between steady state total and unbound disopyramide plasma levels in patients with supraventricular or ventricular arrhythmias, and pharmacologic response as determined by standard intracardiac electrophysiologic studies.