Abstract
Pharmacokinetics and pharmacodynamics were studied in three dogs with interventricular coronary artery ligatures (ligature of Harris) and in three control animals. Weighted nonlinear analysis was used to fit equations describing two and three compartment open models to the experimental data, obtained after intravenous injection (5 mg/kg) of the drug. The three compartment model gave a reduction in the weighted sum of squared residuals and an improvement in the randomness of scatter of the experimental points about the theoretical curve. The postdistribution elimination half-life was longer, the area under the plasma elimination curve larger, and the total body plasma clearance and apparent volume of distribution was reduced in the animals with arrhythmias. The pharmacological response was assessed by recording the ECG and calculating the percentage of normal sinus rhythm/min. A combined pharmacokinetic-pharmacodynamic model was used to analyze data from individual animals. ke0, a measure of the lag time of pharmacological response behind changes in plasma concentration, and Ce (50), a measure of the sensitivity of the cardiac site of action of the drug, were determined.
Similar content being viewed by others
References
G. Bourgery, Ph. Dostert, A. Lacour, M. Langlois, B. Pourrias, J. Tisné-Versailles. Synthesis and antiarrhythmic activity of new benzofuran derivatives.J. Med. Chem. 24:159–167 (1981).
P. D. Thomson, K. L. Melmon, J. A. Richardson, K. Cohn, W. Steinbrunn, R. Cudihee, and M. Rowland. Lidocaine pharmacokinetics in advanced heart failure, liver disease and renal failure in humans.Ann. Intern. Med. 78:499–508 (1973).
C. T. Ueda and B. S. Dzindzio. Quinidine kinetics in congestive heart failure.Clin. Pharmacol. Ther. 23:158–164 (1978).
I. R. Edwards and B. W. Hancock. Correlation between plasma quinidine and cardiac effect.Br. J. Clin. Pharmacol. 1:455–459 (1974).
R. L. Galeazzi, L. Z. Benet, and L. B. Sheiner. Relationship between the pharmacokinetics and pharmacodynamics of procainamide.Clin. Pharmacol. Ther. 20:278–289 (1976).
A. S. Harris. Delayed development of ventricular ectopic rhythms following experimental coronary occlusion.Circulation 1:1318–1328 (1950).
O. W. Schalm.Veterinary Haematology. Lea & Febiger, Philadelphia, 1965, p. 24.
E. Toro-Goyco, B. R. Martin, and L. S. Harris. Binding of 1-α-acetylmethadol and its metabolites to blood constituents.Biochem. Pharmacol. 29:1897–1902 (1980).
M. Gibaldi and D. Perrier.Pharmacokinetics. Marcel Dekker, New York, 1975, pp. 53–55.
M. Gibaldi and D. Perrier.Pharmacokinetics. Marcel Dekker, New York, 1975, pp. 89–95.
W. G. Kramer, A. J. Kolibash, R. P. Lewis, M. S. Bathala, J. A. Visconti, and R. H. Reuning. Pharmacokinetics of digoxin: relationship between response intensity and predicted compartmental drug levels in man.J. Pharmacokin. Biopharm. 7:47–61 (1979).
P. V. Pedersen. Curve fitting and modeling in pharmacbkinetics and some practical experiences with NONLIN and a new program FUNFIT.J. Pharmacokin. Biopharm. 5:513–531 (1977).
K. Yamaoka, T. Nakagawa, and T. Uno. Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations.J. Pharmacokin. Biopharm. 6:165–175 (1978).
H. G. Boxenbaum, S. Riegelman, and R. M. Elashoff. Statistical estimations in pharmacokinetics.J. Pharmacokin. Biopharm. 2:123–148 (1974).
L. B. Sheiner, D. R. Stanski, S. Vozeh, R. D. Miller, and J. Ham. Simultaneous model of pharmacokinetics and pharmacodynamics: application to d-tubocurarine.Clin. Pharmacol. Ther. 25:358–371 (1979).
B. Whiting, N. H. G. Holford, and L. B. Sheiner. Quantitative analysis of the disopyramide concentration-effect relationship.Br. J. Clin. Pharmacol. 9:67–75 (1980).
R. H. De Jong, J. E. Heavner, and L. De Oliveira. Intravascular lidocaine compartment: kinetics of bolus injection.Anesthesiology 37:493–497 (1972).
E. R. Smith and B. R. Duce. Antiarrhythmic effects in dogs of intravenous and oral administration of lidocaine.Circulation 37(suppl. 6):182 (1968).
P. H. Hinderling and E. R. Garrett. Pharmacodynamics of the antiarrhythmic disopyramide in healthy humans: correlation of the kinetics of the drug and its effects.J. Pharmacokin. Biopharm. 4:231–242 (1976).
P. H. Hinderling and E. R. Garrett. Pharmacokinetics of the antiarrhythmic disopyramide in healthy humans.J. Pharmacokin. Biopharm. 4:199–230 (1976).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Dow, J., Laquais, B., Tisne-Versailles, J. et al. Pharmacokinetics and pharmacodynamics of the antiarrhythmic compound MD750819 in dogs with experimentally induced arrhythmias. Journal of Pharmacokinetics and Biopharmaceutics 10, 283–296 (1982). https://doi.org/10.1007/BF01059262
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF01059262