Abstract
A study designed to investigate the relationship between the pharmacokinetics of digoxin and a measure of its pharmacological effect has been conducted. Serum digoxin concentrations and systolic time intervals were measured concurrently in 12 normal male volunteers following a 1.0 mg i.v. bolus injection. The averaged serum digoxin concentration- time and response-time data were analyzed pharmacokinetically using a three-compartment open model and nonlinear least- squares fitting. When only the serum level-time data were analyzed, a close relationship was found between calculated digoxin levels in the slowly distributing (deep) peripheral compartment and response of the heart to digoxin, as measured by changes in the QS2 index δQS2I. Although it was not possible to distinguish clearly a linear from a nonlinear relationship between digoxin levels in the deep compartment and δQS2I, the nonlinear relationship gave the best overall fit when both serum digoxin and δQS2I data were fitted simultaneously. The simultaneous fityielded a total body clearance of digoxin of 3.6 ml/min/kg and a terminal t1/2 of 42 hr.
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R. P. Lewis, R. F. Leighton, W. F. Forester, and A. M. Weissler. Systolic time intervals. In A. M. Weissler (ed.),Noninvasive Cardiology, Grune and Stratton, New York, 1974, pp. 301–368.
A. M. Weissler, J. R. Snyder, C. D. Schoenfeld, and S. Cohen. Assay of digitalis glycosides in man.Am. J. Cardiol. 17:768–780 (1966).
R. P. Lewis, S. E. Rittgers, W. F. Forester, and H. Boudoulas. A critical review of systolic time intervals.Circulation 56:146–158 (1977).
W. G. Kramer, R. P. Lewis, T. C. Cobb, W. F. Forester, J. A. Visconti, L. A. Wanke, H. G. Boxenbaum, and R. H. Reuning. Pharmacokinetics of digoxin: comparison of a two- and a three-compartment model in man.J. Pharmacokin. Biopharm. 2:299–312 (1974).
L. Z. Benet. General treatment of linear mammillary models with elimination from any compartment as used in pharmacokinetics.J. Pharm. Sci. 61:536–541 (1972).
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).
D. L. Voshall, L. Hunter, and H. J. Grady. Effect of albumin on serum digoxin radioimmunoassays.Clin. Chem. 21:402–406 (1975).
C. M. Metzler.NONLIN: A Computer Program for Parameter Estimation in Nonlinear Situations. Technical Report No. 7292/69/7292/005, Upjohn, Kalamazoo, Mich., 1969.
J. G. Wagner.Fundamentals of Clinical Pharmacokinetics, Drug Intelligence Publications, Hamilton, Ill., 1975, pp. 312–318.
R. H. Reuning, R. A. Sams, and R. E. Notari. Role of pharmacokinetics in drug dosage adjustment. 1. Pharmacologic effect kinetics and apparent volume of distribution of digoxin.J. Clin. Pharmacol. 13:127–141 (1973).
R. J. Hoeschen and T. E. Cuddy. Dose-response relation between therapeutic levels of serum digoxin and systolic time intervals.Am. J. Cardiol. 35:469–472 (1975).
R. G. Stoll, M. S. Christensen, E. Sakmar, and J. G. Wagner. The specificity of the digoxin radioimmunoassay procedure.Res. Commun. Chem. Pathol. Pharmacol. 4:503–510 (1972).
W. G. Kramer, M. S. Bathala, and R. H. Reuning. Specificity of the digoxin radioimmunoassay with respect to dihydrodigoxin.Res. Commun. Chem. Pathol. Pharmacol. 14:83–88 (1976).
H. Greenwood, W. Snedden, R. P. Hayward, and J. Landon. The measurement of urinary digoxin and dihydrodigoxin by radioimmunoassay and by mass spectroscopy.Clin. Chim. Acta 62:213–224 (1975).
K. R. H. Repke, I. Herrmann, R. Kunze, H. J. Portius, R. Schön, and W. Schönfeld. Mechanism of digitalis action and the importance of the kinetics of the formation and decomposition of glycoside-receptor complex for understanding of overall pharmacokinetics of digitalis compounds. In O. Storstein (ed.),Symposium on Digitalis, Glydendal Norsk Forlag, Oslo, Norway, 1973, pp. 143–151.
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Supported in part by Philips Roxane Laboratories, Columbus, Ohio, Medicinal Chemistry Training Grant GM-1949 (NIH) for W.G.K, Central Ohio Heart Chapter of AHA and National Heart and Lung Institute Training Grant No. 5-T01-HL05968 for A.J.K., and Clinical Research Center Grant RR-34 (PHS). This article is abstracted in part from a dissertation submitted by W.G.K. to the Graduate School, The Ohio State University, Columbus, Ohio, in partial fulfillment of the Doctor of Philosophy degree requirements.
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Kramer, W.G., Kolibash, A.J., Lewis, R.P. et al. Pharmacokinetics of digoxin: Relationship between response intensity and predicted compartmental drug levels in man. Journal of Pharmacokinetics and Biopharmaceutics 7, 47–61 (1979). https://doi.org/10.1007/BF01059440
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DOI: https://doi.org/10.1007/BF01059440