Abstract
The pharmacokinetics and pharmacodynamics of the antiarrhythmic drug, disopyramide, were investigated in 12 volunteers who took 300 mg doses of 3 different capsule preparations and an aqueous oral solution of the drug at 1-week intervals. Concentrations of drug unbound to plasma proteins were measured by a sensitive immunoenzyme assay after ultrafiltration of plasma samples taken serially after dosing. QT interval was measured on serial ECG recordings with correction for changes in heart rate. Unbound concentrations of disopyramide were modelled by an open one-compartment pharmacokinetic model with a zero-order absorption rate and a lag time. There was no significant difference in parameter estimates between the four preparations, except for the lag time, which was significantly shorter for the solution preparation. The saturable protein binding of disopyramide was described by a hyperbolic model including a specific binding site and additional nonspecific binding. The pharmacodynamic relationship between unbound drug concentration and QT prolongation was fit by a simple linear model. This fit was better using unbound concentration of the drug than using total concentrations.
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References
A. Karim, C. Nissen, and D. L. Azarnoff. Clinical pharmacokinetics of disopyramide.J. Pharmacokin. Biopharm. 10:465–494 (1982).
B. Whiting, N. H. G. Holford, and L. B. Sheiner. Quantitative analysis of the disopyramide concentration effect relationship.Eur. J. Clin. Pharmacol. 9:67–75 (1980).
S. M. Bryson, B. Whiting, and J. R. Lawrence. Disopyramide serum and pharmacologic effect kinetics applied to the assessment of bioavailability.Br. J. Clin. Pharmacol. 6:409–419 (1978).
J. J. Lima, H. Boudoulas, and M. Blanford. Concentration dependence of disopyramide binding to plasma protein and its influence on kinetics and dynamics.J. Pharmacol. Exp. Ther. 219:741–747 (1981).
G. W. Holt, R. L. G. Norris, P. J. Ravenscroft, J. H. N. Bett, L. G. Dryburgh, and C. M. Boyle. Effect of disopyramide on left ventricular performance: The relationship of free and total concentrations of the drug and of its mono-N-dealkylated metabolite to noninvasive indices of function.J. Cardiovasc. Pharmacol. 5:51–54 (1983).
K. M. Giacomini, S. E. Swezey, K. Turner-Tamiyasu, and T. Blaschke. The effect of saturable binding to plasma proteins on the pharmacokinetic properties of disopyramide.J. Pharmacokin. Biopharm. 10:1–14 (1982).
P. Hinderling, J. Bres, and E. Garrett. Protein binding and erythrocyte partitioning of disopyramide and its monodeakylated metabolite.J. Pharm. Sci. 63:1684–1690 (1974).
P. J. Meffin, E. W. Robert, R. A. Winkle, S. Harapat, F. A. Peters, and D. C. Harrison. Role of concentration dependent plasma protein binding in disopyramide disposition.J. Pharmacokin. Biopharm. 7:29–46 (1979).
M. M. Bradford. A rapid sensitive method for quantification of microgram quantities of protein.Anal. Biochem. 72:248–257 (1976).
L. M. Shaw, R. Altman, B. C. Thompson, and L. Fields. Effect of several variables on the in vitro binding of disopyramide to serum proteins.Clin. Pharmacokin. 9:98–99 (1984).
SYVA Corp., unpublished observations.
B. E. Pape. Enzyme immunoassay of disopyramide in serum.Clin. Chem. 27:2038–2040 (1981).
J. D. Huang and S. Øie. Effect of altered disopyramide binding on its pharmacologic response in rabbits.J. Pharmacol. Exp. Ther. 223:469–471 (1982).
L. B. Sheiner and S. L. Beal. Estimation of pooled pharmacokinetic parameters describing population. In Laszlo Endrenyi (ed.),Kinetic Data Analysis. Plenum Press, New York, 1981, pp. 271–284.
N. H. G. Holford and L. B. Sheiner. Understanding the dose-effect relationship.Clin. Pharmacokin. 6:429–452 (1981).
C. Peck, L. B. Sheiner, and A. I. Nichols. The problem of choosing weights in nonlinear regression analysis of pharmacokinetic data.Drug Metab. Rev. 15:133–148 (1984).
W. F. Raub. The PROPHET computer system and resource sharing.Fed. Proc. 33:2390 (1976).
N. H. G. Holford. MKMODEL, a mathematical modelling tool for the Prophet computer system. In H. M. Perry (ed.),Prophet Public Procedures Notebook, Bolt Beranek and Newman Inc., Cambridge, Mass., 1982, pp. 85–145.
G. Schwartz. Estimating the dimensions of a model.Ann. Stat. 6:461–464 (1978).
J. L. Cunningham, D. D. Shen, I. Shudo, and D. L. Azarnoff. The effects of urine pH and plasma protein binding on the renal clearance of disopyramide.Clin. Pharmacokin. 2:373–383 (1977).
M. L. Aito. Plasma concentrations and protein binding of disopyramide and mono-N-dealkyldisopyramide during chronic oral disopyramide treatment.Br. J. Clin. Pharmacol. 11:369–376 (1981).
B. M. David, B. W. Madsen, and K. F. Ilett. Plasma binding of disopyramide.Br. J. Clin. Pharmacol. 9:614–618 (1980).
S. M. Bryson, J. R. Lawrence, W. H. Steele, B. C. Campbell, H. L. Elliott, and D. J. Summer. The influence of protein binding on disopyramide clearance.Eur. J. Clin. Pharmacol. 23:453–456 (1982).
R. L. G. Norris, J. T. Ahokas, and P. J. Ravenscroft. Determination of unbound fraction of disopyramide in plasma: A comparison of equilibrium dialysis, ultrafiltration through dialysis membranes and ultrafree anticonvulsant drug filters.J. Pharmacol. Methods 7:143–149 (1982).
T. N. Tozer, J. G. Gambertoglio, D. E. Furst, D. S. Avery, and N. H. G. Holford. Volume shift and protein binding estimates using equilibrium dialysis: application to prednisolone binding in humans.J. Pharm. Sci. 72:1442–1446 (1983).
N. H. G. Holford, P. S. Lizak, and J. G. Gambertoglio. Influence of the error model on the estimation of prednisolone protein binding in man. American Society for Clinical Pharmacology and Therapeutics 84th meeting, 1983, San Diego, Calif., Abstract A 49.Clin. Pharm. Ther. 33:201 (1983).
P. H. Hinderling and E. R. Garrett. Pharmacokinetics of the antiarrhythmic disopyramide in healthy humans.J. Pharmacokin. Biopharm. 4:199–230 (1976).
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Supported in part by grant NIH G.M. 28072 and the PROPHET project of the NIH Biotechnology Resources Group (Proc. Natl. Comp. Conf. Exp. 43:457, 1974). M. Thibonnier is the recipient of a Merck Company Foundation International Fellowship in Clinical Pharmacology.
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Thibonnier, M., Holford, N.H.G., Upton, R.A. et al. Pharmacokinetic-pharmacodynamic analysis of unbound disopyramide directly measured in serial plasma samples in man. Journal of Pharmacokinetics and Biopharmaceutics 12, 559–573 (1984). https://doi.org/10.1007/BF01059552
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DOI: https://doi.org/10.1007/BF01059552