Single and multiple dose pharmacokinetics of oral quinidine sulfate and gluconate

Abstract

The pharmacokinetics of oral quinidine sulfate and quinidine gluconate were compared in seven healthy volunteers In a two part pharmacokinetic study. Part I was a single dose crossover trial assessing absorption and elimination of quinidine sulfate (400 mg, equivalent to 331 mg of quinidine base) and quinidine gluconate (495 mg, equivalent to 309 mg of quinidine base). Mean kinetic values for the sulfate and gluconate preparations, respectively, were: peak serum quinidine level 2.07 versus 1.24 μg/ml ( P < 0.025); time of peak concentration 1.61 versus 3.64 hours after the dose ( P < 0.02); first order absorption half-life 41.1 versus 61.2 minutes ( P < 00.1); elimination half-life 6.1 versus 6.3 hours (difference not significant); absolute systemic availability (based upon comparison with intravenous data from the same subjects) 86.0 versus 76.5 percent (difference not significant) using area under the serum concentration curve, or 83.7 versus 73.6 percent ( P < 0.05) using cumulative 48 hour urinary excretion of quinidine. The findings indicate that absorption of quinidine gluconate is slightly less complete but much less rapid than that of quinidine sulfate. Part II evaluated steady state kinetics of both preparations in a cross-over trial in the same subjects. Maintenance dosing schedules were 200 mg of quinidine sulfate every 6 hours versus 495 mg of quinidine gluconate every 12 hours. Systemic availability of the gluconate at the steady state level was 10 percent less (based upon area under the serum concentration curve) or 7 percent less (based upon urinary excretion of quinidine) than that of the sulfate, but the differences were not significant. Interdose fluctuation in serum quinidine concentrations during the gluconate trial averaged 70 percent, which was not significantly different from the average of 67 percent during the sulfate trial. However, variation within and between subjects in minimal steady state levels with quinidine gluconate (15.6 and 16.0 percent, respectively) was greater than with quinidine sulfate (7.2 and 9.9 percent, respectively). Steady state concentrations during the multiple dose trial were not accurately predicted from single dose pharmacokinetics, either for quinidine sulfate ( r = 0.45) or quinidine gluconate ( r = −0.12), but deviation of observed from predicted concentrations tended to be greater with quinidine gluconate. The slow absorption of quinidine from the gluconate preparation allows maintenance therapy on a 12 hourly dosage schedule with acceptable interdose fluctuation in serum levels. Variability within and between subjects in absorption kinetics tends to be greater with quinidine gluconate than with the more rapidly absorbed sulfate salt.