Pharmacokinetics of disopyramide in patients with chronic renal failure

Abstract

The pharmacokinetics study of a single oral dose of 200 mg of disopyramide was performed in 22 normal control subjects and 33 patients with chronic renal failure (CRF). The latter were subdivided into 3 groups of 11 patients each as a function of the gravity of renal insufficiency. With the exception of maximum concentration (C max), which was only slightly modified, and of the apparent distribution volume which remained unchanged, all the other pharmacokinetic blood parameters (t max, concentration at 24th hour, elimination constant (ke h-1), elimination half-life, area under the curve and plasma clearance) were significantly modified in the CRF group; in particular, the elimination half-life was significantly increased (for 22 cases of CRF with mean plasma creatinine greater than 250 microM at 16.3 hours compared to 8.0 hours in controls). The urinary elimination of disopyramide was studied in 14 renal insufficiency patients and in 6 controls. The decreased rate of urinary excretion of disopyramide and its monodealkylated derivative (NMD), during the first 24 hours, was directly related to the severity of renal insufficiency. The ratio of urinary NMD/(disopyramide + NMD) was unchanged in CRF patients as compared to the controls. The results suggest that the dosage of disopyramide should be decreased when plasma creatinine values are greater than 250 microM, and creatinine clearance is less than 30 ml/min. The dose for a 70 kg subject would be 100 mg, administered every 12 hours.

Effect of Renal Impairment on the Pharmacokinetics of Disopyramide and Its Metabolite and Serum Insulin Level: A Single Dose Study

“…In our ／ present study, mean CL／F and t1/2 of disopyramide ／ varied from 5263 mL／h and 9.95 hours in mild renal ／ function impairment to 3428 mL／h and 14.47 h in severe renal function impairment, respectively, and in ／ healthy 12 Japanese subjects mean CL／F and t1/2 ／ were reported to be 6173 mL／h and 6.05 h, respectively 12) . These results were in line with the study reported by Francois et al 2) . Since disopyramide Cmax was not affected, renal function impairment would affect disopyramide elimination from the body but not its absorption.…”

“…As reported in previous studies in Caucasian population 2,3) , renal function impairment affected the pharmacokinetics of disopyramide and its metabolite, monoisopropyl disopyramide. In our ／ present study, mean CL／F and t1/2 of disopyramide ／ varied from 5263 mL／h and 9.95 hours in mild renal ／ function impairment to 3428 mL／h and 14.47 h in severe renal function impairment, respectively, and in ／ healthy 12 Japanese subjects mean CL／F and t1/2 ／ were reported to be 6173 mL／h and 6.05 h, respectively 12) .…”

“…At 24 hours after oral administration, 40-50％ of the single dose administered were excreted into the urine in the form of 75％ disopyramide and 25％ a major metabolite, monoisopropyldisopyramide in healthy subjects 2) . Therefore, the adjustment of dosage is recommended in patients with renal failure 2,3) in order to prevent a rise in plasma concentrations leading to adverse reactions of disopyramide such as excessive QT interval prolongation of the ECG, negative inotropic effect, and anticholinergic effect 1) . In addition to those undesirable effects, hypoglycemia has been reported to develop following the treatment with disopyramide 4,5) .…”

Clinical Pharmacokinetics of Disopyramide

“…However, MND concentration would be expected to be only about 0.5 mgfL in this setting (Aitio et al 1981), and a contribution of MND to disopyramide's pharmacological effects therefore cannot be excluded by this study. Single-dose studies of disopyramide pharmacokinetics in patients with renal failure have shown that although maximum concentration achieved after an oral dose is little changed, there is substantial difference in other parameters (Burk & Peters 1983;Francois et al 1983). Time to maximum concentration following an oral dose (tmaJ is increased by approximately 50% in the presence of renal failure, and volume of distribution (V d) is reduced by one-third.…”