Summary
Quinidine and one of its major metabolites, quinidine-N-oxide, were given by separate i.v. infusions to each of three beagle dogs. Plasma and urine samples were analysed for pharmacokinetic comparison of the drug and its metabolite. Quinidine apparently distributed into two major compartments, while the N-oxide distributed into three compartments. The compartment-independent pharmacokinetic parameters (mean ± SD) were for quinidine Vdss 4.78±1.1 l/kg, clearance 0.074±0.047 l/min, terminal half-life 720±343 min and for quinidine-N-oxide Vdss 1.03±0.21 l/kg, clearance 0.065±0.012 l/min, terminal half-life 316±69 min. Only 29% of quinidine was recovered in the urine as unchanged drug while 77% of the N-oxide was excreted unchanged via the kidney. Non-linear renal elimination of the N-oxide was observed in two out of three dogs with a Michaelis-Menten constant, KM of about 7 μg/ml (21 μM).
Prolongation of the QT-interval in the ECG response was used for comparing pharmacodynamic effects. Quinidine was about three to four fold more active than the N-oxide at similar plasma concentrations. Quinidine-N-oxide concentrations in plasma after quinidine administration were very low and would not contribute significantly to the quinidine effect.
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This publication is based in part, on the thesis submitted by Dr. A Rakhit to the University of California, San Francisco in partial fulfillment of the requirement for the degree of Doctor of Philosophy.
Professor Sidney Riegelman deceased April 4, 1981.
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Rakhit, A., Guentert, T.W., Holford, N.H.G. et al. Pharmacokinetics and pharmacodynamics of quinidine and its metabolite, quinidine-N-oxide, in beagle dogs. European Journal of Drug Metabolism and Pharmacokinetics 9, 315–324 (1984). https://doi.org/10.1007/BF03189683
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DOI: https://doi.org/10.1007/BF03189683