Kinetics and dynamics of disopyramide and its dealkylated metabolite in healthy subjects

Abstract

The kinetics and dynamics of total and free (unbound) disopyramide (D) after dosing with D, 1.5 and 2 mg/kg iv, were compared with those of the dealkylated metabolite (MND) after dosing with MND, 0.5 and 1.5 mg/kg iv, in six healthy subjects. Dynamic parameters included ECG with measurement of the QT interval corrected for heart rate (QTc), systolic time intervals, vitamin C-stimulated saliva secretion, pupil size, and maximum accommodation capacity. Mean values of total clearance, apparent volume of distribution, and elimination t1/2 of MND were 5.9, 2.3, and 0.4 times those of total D, respectively. D significantly prolonged the QTc and systolic time intervals and induced transient inhibition of stimulated saliva secretion. In contrast, MND induced no substantial change in either the QTc or systolic time intervals, but did induce more persistent inhibition of salivary secretion. If anticholinergic potency is determined as the degree of inhibition of stimulated saliva flow per plasma concentration unit, MND was three times as potent as its parent when measured at maximum inhibition. There were no consistent drug effects on the ocular parameters. The effect of D on QTc correlated with both total and free plasma concentrations. Furthermore, its transient salivary inhibitory effect paralleled its initial rapid decline in plasma concentration. There was no relationship between the MND plasma concentration and its salivary inhibitory effect. We conclude that disopyramide significantly affected the QTc and systolic time intervals in healthy subjects, while MND in a similar dose had no such effects. MND more strongly inhibited stimulated saliva flow, indicating a more potent anticholinergic effect than D.

Free Drug Concentration Monitoring in Clinical Practice

“…Available data from humans support these findings. For example, it has been shown that better linear relationships exist between free disopyramide concentrations (than total drug) and measured pharmacological response, including change in QT c (Chiang et al 1985;Thibonnier et al 1984) and negative inotropic effect (Chiang et al 1985;Holt et al 1983b;Lima et al 1981;Pollick et al 1982). Thus, when monitoring disopyramide plasma concentration, it appears that it may be more relevant to monitor free rather than total concentration.…”

“…It has the interesting property of concentration-dependent binding at therapeutic plasma concentrations (Hinderling & Garrett 1976). The disopyramide free fraction has been reported to vary from 0.10 to 0.40 over a given dosage interval in an individual (Bredesen et al 1982;Bredesen & Kierulf 1984;Chiang et al 1985). Thus, the clearance of total disopyramide exhibits apparent dose-dependent behaviour (Hinderling & Garrett 1976), while clearance of unbound disopyramide is a nearly linear function of dose (Lima et al 1981;Meffin et al 1979).…”

“…MND has been shown to have minimal effect against ventricular arrhythmias compared with disopyramide (Chiang et al 1985;Karim et al 1982), although in severe renal failure accumulation of MND may give rise to pharmacologically important concentrations. More recent work in patients and volunteers has shown that total concentration of disopyramide is correlated with changes in QTc (Bryson et al 1978;Chiang et al 1985;Hinderling & Garrett 1976;Whiting et al 1980) and the reduction in the frequency of ventricular ectopic beats (Ueda et al 1984). Thus, monitoring of total disopyramide concentration to optimise pharmacological effect is supported by experimental data from humans.…”

Comparative class 1 electrophysiologic and anticholinergic effects of disopyramide and its main metabolite (mono-N-dealkylated disopyramide) in healthy humans

“…It is excreted in the urine mostly unchanged, but 20-50% is metabolized. Considering the pharmacological activity of the metabolite, as observed in experimental models and noninvasively in humans [3][4][5], it could be assumed to contribute significantly to the effects during maintenance t r e a tment with disopyramide in individual patients. The steadystate ratio of the metabolite to the p a r e n t drug ranged between 0.06 and 4.0 in the plasma of 70 patients and was ->1.0 in more than 25% of patients [2].…”

“…The major metabolite is des-isopropyldisopyramide, usually called mono-N-dealkylated disopyramide [1]. However, neither the class 1 electrophysiologic effects of the metabolite nor its anticholinergic actions, claimed to be 3-24 times more pronounced than those of the parent drug [3,4], have been appropriately assessed by invasive electrophysiologic methods in human beings. Considering the pharmacological activity of the metabolite, as observed in experimental models and noninvasively in humans [3][4][5], it could be assumed to contribute significantly to the effects during maintenance t r e a tment with disopyramide in individual patients.…”