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

Preexisting chronic renal failure is a major risk factor of disopyramide-induced hypoglycemia because renal excretion plays a major role in the elimination of disopyramide from systemic circulation. We evaluated the effect of renal failure on the pharmacokinetics of disopyramide, and examined the relationship between plasma disopyramide concentration and serum level of glucose or insulin. Seventeen subjects with mild to severe chronic renal impairment estimated by the Cockcroft-Gault method and without arrhythmia were enrolled and administered a single oral dose of 100 mg disopyramide after overnight fasting. Four and 24-hour creatinine clearance correlated significantly with AUC (r=0.620 and 0.554 for 4-hour and 24-hour methods, respectively), CL/F (r=0.553 and 0.520) and t1/2 (r=0.584 and 0.616) of disopyramide, as well as AUC (r=0.625 and 0.532) and t1/2 (r=0.611 and 0.670) of monoisopropyl disopyramide, the major metabolite, but did not correlate with Cmax of disopyramide or its metabolite. Serum concentration of alpha-1 acid glycoprotein (AAG) correlated significantly with the pharmacokinetic parameters of disopyramide. Both serum glucose and insulin levels decreased significantly 4 hours after disopyramide administration compared to before dosing, and a weak but significant correlation was observed between plasma disopyramide concentration and the change in serum insulin level (r=0.373), but not the change in serum glucose level. In conclusion, disopyramide pharmacokinetics is affected not only by renal function impairment, but also by serum AAG concentration. In addition to severe renal function impairment, higher serum AAG concentration may be a risk factor that elevates plasma disopyramide concentration and induces toxic effects.