Pharmacokinetics of quinidine and three of its metabolites in man

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Abstract
Disposition parameters of quinidine and three of its metabolites, 3-hydroxy quinidine, quinidine N-oxide, and quinidine 10,11-dihydrodiol, were determined in five normal healthy volunteers after prolonged intravenous infusion and multiple oral doses. The plasma concentrations of individual metabolites after 7 hr of constant quinidine infusion at a plasma quinidine level of 2.9±(SD) 0.3 mg/L were: 3-hydroxy quinidine, 0.32±0.06 mg/L; quinidine N-oxide, 0.28±0.03 mg/L; and quinidine 10,11-dihydrodiol, 0.13±0.04 mg/L. Plasma trough levels after 12 oral doses of quinidine sulfate every 4 hr averaged: quinidine, 2.89±0.50 mg/L; 3-hydroxy quinidine, 0.83±0.36 mg/L; quinidine N-oxide, 0.40±0.13 mg/L; and quinidine 10,11-dihydrodiol, 0.38±0.08 mg/L. Relatively higher plasma concentrations of 3-hydroxy quinidine metabolite after oral dosing probably reflect first-pass formation of this quinidine metabolite. A two-compartment model for quinidine and a one-compartment model for each of the metabolites described the plasma concentration-time curves after both i.v. infusion and multiple oral doses. Mean (±SD) disposition parameters for quinidine from individual fits, after i.v. infusion were as follows: V 1 ,0.37±0.09 L/kg; λ1,0.094±0.009 min −1; λ2, 0.0015±0.0002 min−1; EX2, 0.013±0.002 min−1;clearance (ClQ),3.86±0.83 ml/min/kg. Both plasma and urinary data were used to determine metabolic disposition parameters. Mean (±SD) values for the metabolites after i.v. quinidine infusion were as follows: 3-hydroxy quinidine: formation rate constant kmf,0.0012±0.0005 min −1,volume of distribution, Vm,0.99±0.47 L/kg; and elimination rate constant, kmu 0.0030±0.0002 min −1.Quinidine N-oxide: kmf,0.00012±0.00003 min −1; Vm,0.068±0.020 L/kg; and kmu,0.0063±0.0008 min −1.Quinidine 10,11-dihydrodiol: kmf,0.0003±0.0001 min −1; Vm,0.43±0.29 L/kg; and kmu,0.0059±0.0010 min −1.Oral absorption of quinidine was described by a zero order process with a bioavailability of 0.78. Concentration dependent renal elimination of 3-hydroxy quinidine was observed in two out of five subjects studied.