Plasma concentrations and protein binding of disopyramide and mono‐N‐ dealkyldisopyramide during chronic oral disopyramide therapy.

Abstract

1 The plasma levels of disopyramide and mono-N-dealkyldisopyramide were measured from 118 patients, and the protein binding of both drugs from 50 patients during chronic oral disopyramide therapy. 2 No significant correlation was seen between the daily dose of disopyramide and the achieved plasma drug concentration. 3 The concentration of mono-N-dealkyldisopyramide in the plasma was about one third of that of disopyramide in patients with normal renal function. 4 The mean plasma levels of disopyramide and mono-N-dealkyldisopyramide were high in patients with renal impairment. In patients with simultaneous therapy with enzyme inducing drugs the mean levels of disopyramide were low and those of mono-N-dealkyldisopyramide high. 5 In patients with effective treatment of ventricular arrhythmias the levels of disopyramide were significantly higher than in those with ineffective treatment; the difference was not significant in supraventricular arrhythmias. Patients with side-effects had slightly though not significantly higher disopyramide levels than patients without side-effects; mono-N-dealkyldisopyramide concentrations were identical. 6 The average protein binding of disopyramide was 82%, and that of mono-N-dealkyldisopyramide 22-35%. Although a concentration dependent binding of disopyramide was seen within an individual, the average protein binding did not vary significantly at different concentrations of all samples analyzed. The protein binding was not altered in renal insufficiency, but was slightly decreased by high concentrations of mono-N-dealkyldisopyramide.

Relationship between alpha 1‐acid glycoprotein and distribution of disopyramide and mono‐N‐dealkyldisopyramide in whole blood.

“…There was a negative linear relationship between the AAG concentration and the B/P ratio in the 50 patient samples for DP (r = -0.8583) and MND (r = -0.7888) as well as in the samples from the five healthy subjects (r = -0.8800 and r = .0. (Aitio 1981;Bredesen et al, 1982;David et al, 1983). Two recent studies indicated that al-acid glycoprotein (AAG) was the major protein, and probably the only one responsible for the binding of DP and MND (Pike et al, 1983;Bredesen & Kierulf, 1984).…”

“…Dealky-appears in the urine as MND. The serum conlation to the pharmacologically active metabolite centration of MND in patients on maintenance 281 treatment with DP, may even be higher than that of the parent drug (Aitio, 1981;Bredesen et al, 1982).…”

Relationship between alpha 1‐acid glycoprotein and plasma binding of disopyramide and mono‐N‐dealkyldisopyramide.

“…Wide interindividual binding variations of DP have been reported by a number of authors (Aitio, 1981;Bredesen et al, 1982;David et al, 1983 reported that albumin was the main (Bredesen et al, 1982). Fourteen of the 60 protein whereas Lima & Salzer (1981) samples had higher concentrations of MND I that only 5-10% was bound to than DP.…”

“…concentrations of MND in some patients on About 55% of the administered dose of DP is maintenance treatment with DP, were even eliminated unchanged, primarily by the kidneys. higher than that of the parent drug (Aitio, 1981; The main metabolic pathway of DP is dealkyla -Bredesen et al, 1982). tion to the pharmacologically active metabolite, The plasma protein binding of both DP and mono-N-dealkyldisopyramide, and about 25% MND shows a wide intersubject and concentraof the administered drug is excreted by the tion dependent variability even within the kidneys as MND.…”

The effect of enzyme induction on the metabolism of disopyramide in man.

“…There is, however, not always any correlation between the production of D-glucaric acid and enzyme induction (Marselos, Torronen & Aitio, 1978;Freundt, 1979). Chronic disopyramide therapy lasting over 10 days caused a slight decrease in the disopyramide plasma levels in a patient series (Aitio, 1981). In the rat a strong enzyme inducer, phenobarbitone, caused an about four-fold increase in the metabolism of disopyramide, whereas disopyramide proved to be a weak inducer of its own metabolism (Aitio & Aitio, 1979).…”