Influence of concentration‐dependent protein binding on serum concentrations and urinary excretion of disopyramide and its metabolite following oral administration

Concentrations of disopyramide (D) and mono‐N‐dealkyldisopyramide (MND) were measured in serum and urine following administration of 100, 150, 200, and 300 mg D to four volunteers. The free fraction of D in serum was drug concentration‐dependent in all four subjects following the administration of the four doses. Areas under the free (unbound) D serum concentration‐time curves (AUC   0–9 free ) were linearly related to dose following 100–200 mg D. AUC   0–9 freevalues were 30–60 per cent higher than expected in two subjects following 300 mg D due to an apparent dose‐dependent decrease in D renal tubular secretion. Renal clearance of free D averaged 10·91h −1 . The renal clearance of MND averaged 10·31h −1 . The urinary excretion of MND was proportional to disopyramide dose.