Disopyramide pharmacokinetics and bioavailability following the simultaneous administration of disopyramide and14C-disopyramide

Abstract

The pharmacokinetics and bioavailability of total (bound plus unbound) and unbound disopyramide were compared following the simultaneous administration of an oral dose of disopyramide and an intravenous dose of 14C-disopyramide in five normal volunteers and in 11 patients with congestive heart failure. The binding of disopyramide varied between 60 and 92% in patients and between 81 and 88% in normal subjects at postequilibrium drug concentrations of 10(-7) M. The binding of disopyramide to serum protein was concentration-dependent in all study subjects at serum concentrations achieved following drug administration. The association constant for the first binding site in serum from normal subjects and patients averaged 8.7 X 10(5) M-1 and 4.4 X 10(5) M-1, respectively (p less than 0.05). The unbound clearance of disopyramide averaged 277 ml/min and 209 ml/min in normal subjects and in patients (p less than 0.05). When normalized for body weight, the unbound clearance between patients and normal subjects was not significantly different. The elimination half-life of unbound concentrations in normal subjects and in patients averaged 4.9 and 6.1 h, respectively (p less than 0.05). The clearance and elimination half-life of total disopyramide was the same in both groups. Although the bioavailability of disopyramide averaged 0.85 in both groups, it was more variable in patients owing to the variability in the fraction of the dose absorbed. The unbound renal clearance and volume of distribution at steady state of disopyramide was related to cardiac index. The ratio of elimination half-lives of total and unbound disopyramide was related to the extent of serum protein binding.

Effects of Serum Concentrations of Disopyramide and Its Metabolite Mono-N-dealkyldisopyramide on the Anticholinergic Side Effects Associated with Disopyramide

“…These results suggest that the effect of renal function on the C/D of MND is larger that that of DP, and that not DP concentration but MND concentration should be monitored in patients whose renal functions are decreased. Approximately 50% of DP is excreted unchanged in the urine, 4) and partly metabolized to MND. The conversion of DP to MND is mainly catalyzed by CYP3A4.…”

“…6) The elimination half-life (t 1/2 ) of DP is within 6 to 8 h, 4) approximately 30-70% DP is bound to proteins, and the affinity for a 1 -acid glycoprotein is higher than that for albumin. 7) MND accumulation is expected in renal failure.…”

“…The conversion of DP to NMD is mainly catalyzed by CYP3A4.6) The elimination half-life (t 1/2 ) of DP is within 6 to 8 h, 4) approximately 30-70% DP is bound to proteins, and the affinity for a 1 -acid glycoprotein is higher than that for albumin.7) MND accumulation is expected in renal failure.8) Previous studies have suggested that DP and MND have anticholinergic effects such as dry mouth and dysuria, and that the effect of MND is stronger than that of DP. …”

“…

Disopyramide (DP) is a class I antiarrhythmic agent widely used clinically for the treatment and prophylaxis of supraventricular and ventricular arrhythmias.1,2) The antiarrhythmic effect is proportional to the DP serum concentration, and the effective therapeutic range may be from 2 to 5 mg/ml.3) Approximately 50% of DP is excreted unchanged in the urine, 4) and partly metabolized to mono-N-dealkyldisopyramide (MND), 5) the major metabolite of DP in humans. The conversion of DP to NMD is mainly catalyzed by CYP3A4.

6) The elimination half-life (t 1/2 ) of DP is within 6 to 8 h, 4) approximately 30-70% DP is bound to proteins, and the affinity for a 1 -acid glycoprotein is higher than that for albumin.

7) MND accumulation is expected in renal failure.

8) Previous studies have suggested that DP and MND have anticholinergic effects such as dry mouth and dysuria, and that the effect of MND is stronger than that of DP.

9)

However, while there are several reports on DP-or MND induced anticholinergic effect in clinical studies, 10,11) no reports have suggested the safety range of DP or MND for the prevention of the anticholinergic side effects associated with DP.

The aim of this study was to evaluate the relationship between the anticholinergic side effects and serum DP or MND concentration and the safety range of DP or MND for the prevention of their anticholinergic side effects in a clinical study.

MATERIAL AND METHODS

Materials DP, and MND and 4-methylmexiletine were provided by Chugai Pharmaceutical Co., Ltd. (Tokyo, Japan) and Boehringer Ingelheim Co., Ltd. (Hyogo, Japan), respectively.

…”

“…3) Approximately 50% of DP is excreted unchanged in the urine, 4) and partly metabolized to mono-N-dealkyldisopyramide (MND), 5) the major metabolite of DP in humans. The conversion of DP to NMD is mainly catalyzed by CYP3A4.…”