Pharmacokinetics of quinidine and three of its metabolites in man |
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Authors: | Ashok Rakhit Nicholas H G Holford Theodore W Guentert Kathy Maloney Sidney Riegelman |
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Institution: | (1) Drug Metabolism, CIBA-GEIGY Corp., 10502 Ardsley, NY;(2) Department of Pharmacology and Clinical Pharmacology, University of Auckland Medical School, Auckland, New Zealand;(3) School of Pharmacy, University of Basel, and F. Hoffman-La Roche Co., Basel, Switzerland;(4) Department of Clinical Pharmacy, Ives Laboratories, 10017 New York, N.Y. |
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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
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,0.37±0.09 L/kg; 1,0.094±0.009 min
–1; 2, 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.This work was supported by funds from the grants GM 26691 and GM 28072 from the National Institute of General Medical Sciences, NIH. A. Rakhit was the recipient of a Training Grant Traineeship from NIH. T. W. Guentert is grateful for support from the Swiss National Science Foundation.Professor Sidney Riegelman. deceased April 4, 1981. |
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Keywords: | quinidine metabolites intravenous oral pharmacokinetic models humans |
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