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Effect of Concentration-Dependent Binding to Plasma Proteins on the Pharmacokinetics and Pharmacodynamics of Disopyramide

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Summary

Disopyramide exhibits concentration-dependent binding to plasma proteins at therapeutic plasma concentrations. This paper reviews the effect of this type of binding on both the pharmacokinetic and pharmacodynamic properties of the drug. For a drug with capacity-limited, binding-sensitive elimination like disopyramide, concentration-dependent binding to plasma proteins produces a non-linear relationship between dosing rate and total plasma concentrations of the drug. However, when dosing rate is related to unbound concentrations of drug, the relationship is linear. Renal clearance of total disopyramide has been found to depend on the unbound fraction whereas renal clearance of unbound drug may be dependent upon time after drug administration as well as route of drug administration. However, due to some potential methodological problems, these data need verification. The concentration-dependent binding of disopyramide to plasma proteins, with its resultant effects on clearance and distribution, produces a concave curvature in the log unbound concentration versus time curves and a log-linear decline in total plasma concentration versus time after intravenous administration of the drug.

Several pharmacological studies suggest that the unbound drug is active in terms of producing both desirable and undesirable effects. Hence, monitoring unbound concentrations of disopyramide seems more rational for clinical purposes. The few studies that have been carried out examining the optical isomers of disopyramide have suggested that both the pharmacokinetic and pharmacodynamic properties of the drug are stereoselective. Recent data reveal stereoselective binding to plasma proteins in humans. Since disopyramide is administered as a racemic mixture, further work is needed to characterise the relationship between the pharmacokinetics and the pharmacological effects of the individual isomers.

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References

  • Aitio, M.L.: Plasma concentrations and protein binding of diso-pyramide and mono-N-dealkyldisopyramide during chronic oral disopyramide therapy. British Journal of Clinical Pharmacology 11: 369–375 (1981).

    Article  PubMed  CAS  Google Scholar 

  • Bryson, S.M.; Whiting, B. and Lawrence, J.R.: Disopyramide serum and pharmacologie effect kinetics applied to the assessment of bioavailability. British Journal of Clinical Pharmacology 6: 409–419 (1978).

    Article  PubMed  CAS  Google Scholar 

  • Bryson, S.M.; Lawrence, J.R.; Steele, W.H.; Campbell, B.C.; Elliott, H.L. and Sumner, D.J.: The influence of protein binding on disopyramide clearance. European Journal of Clinical Pharmacology 23: 453–456 (1983).

    Article  Google Scholar 

  • Cunningham, J.L.; Shen, D.D.; Shudo, I. and Azarnoff, D.L.: The effect of urine pH and plasma protein binding on the renal clearance of disopyramide. Clinical Pharmacokinetics 2: 373–383 (1977).

    Article  PubMed  CAS  Google Scholar 

  • Cunningham, J.L.; Shen, D.D.; Shudo, I. and Azarnoff, D.L.: The effect of nonlinear disposition kinetics on the systemic availability of disopyramide. British Journal of Clinical Pharmacology 5: 343–346 (1978).

    Article  CAS  Google Scholar 

  • Giacomini, K.M.; Abang, A. and Blaschke, T.F.: Calculation of drug concentration in plasma after equilibrium dialysis. British Journal of Clinical Pharmacology 14: 752–754 (1982a).

    Article  PubMed  CAS  Google Scholar 

  • Giacomini, K.M.; Cox, B.M. and Blaschke, T.F.: Comparative anticholinergic potencies of R and S disopyramide in longitudinal muscle strips from guinea pig ileum. Life Sciences 27: 1191–1195 (1980a).

    Article  PubMed  CAS  Google Scholar 

  • Giacomini, K.M.; Giacomini, J.C.; Swezey, S.E.; Harrison, D.C.; Nelson, W.L.; Burke, T.R. and Blaschke, T.F.: Stereoselective disposition of disopyramide in the dog. Journal of Cardiovascular Pharmacology 2: 825–832 (1980b).

    Article  PubMed  CAS  Google Scholar 

  • Giacomini, K.M.; Swezey, S.E.; Turner-Tamiyasu, K. and Blaschke, T.F.: The effect of saturable binding to plasma proteins on the pharmacokinetic properties of disopyramide. Journal of Pharmacokinetics and Biopharmaceutics 10: 1–14 (1982b).

    PubMed  CAS  Google Scholar 

  • Hillis, W.S.; Tweddel, A.; Lorimer, A.R. and Lawrie, T.D.V.: Some aspects of the clinical pharmacology of intravenous disopyramide after myocardial infarction. Journal of International Medical Research 4 (Suppl. 1): 74–77 (1976).

    PubMed  CAS  Google Scholar 

  • Hinderling, P.H.; Bres, J. and Garrett, E.R.: Protein binding and erythrocyte partitioning of disopyramide and its monodeal-kylated metabolite. Journal of Pharmaceutical Sciences 63: 1684–1690 (1974).

    Article  PubMed  CAS  Google Scholar 

  • Hinderung, PH. and Garrett, E.R.: Pharmacokinetics of the anti-arrhythmic disopyramide in healthy humans. Journal of Pharmacokinetics and Biopharmaceutics 4: 199–230 (1976).

    Google Scholar 

  • Huang, J.D. and Øie, S.: Effect of altered disopyramide binding on its pharmacologie response in rabbits. Journal of Pharmacology and Experimental Therapeutics 223: 469–471 (1982).

    PubMed  CAS  Google Scholar 

  • Karim, A.: The pharmacokinetics of Norpace. Angiology 26 (Suppl. 1, part 2): 85–98 (1975).

    PubMed  CAS  Google Scholar 

  • Lawrence, J.R.; Bryson, S.M.; Sumner, D.J.; Campbell, B.C. and Whiting, B.: The renal clearance of disopyramide after bolus intravenous injection. Biopharmaceutics and Drug Disposition 1: 51–57 (1979).

    Article  CAS  Google Scholar 

  • Lima, J.J.; Boudoulas, H. and Blanford, M.: Concentration-dependence of disopyramide binding to plasma protein and its influence on kinetics and dynamics. Journal of Pharmacology and Experimental Therapeutics 219: 741–747 (1981).

    PubMed  CAS  Google Scholar 

  • Lima, J.J. and Haughey, D.B.: Disopyramide binding to serum protein in man and animals. Drug Metabolism and Disposition 9: 582–583 (1981).

    PubMed  CAS  Google Scholar 

  • Meffin, P.J.; Robert, E.W.; Winkle, R.A.; Harapat, S.; Peters, F.A. and Harrison, D.C.: The role of concentration-dependent plasma protein binding in disopyramide disposition. Journal of Pharmacokinetics and Biopharmaceutics 7: 29–46 (1979).

    PubMed  CAS  Google Scholar 

  • Nelson, W.L.; Sneed, C.K.; Giacomini, K.M.; Gaicomini, J.C.; Stauss, J.; Blaschke, T.F. and Cox, B.M.: Synthesis and anticholinergic properties of the enantiomers of 4- (isopropylam-ino)-2- (2-pyridyl)-2-phenylbutyramide, the mono-N-dealky-lated metabolite of disopyramide. Journal of Medicinal Chemistry 24: 614–617 (1981).

    Article  PubMed  CAS  Google Scholar 

  • Øie, S.; Guentert, T.W. and Tozer, T.N.: Effect of saturable binding on the pharmacokinetics of drugs: A simulation. Journal of Pharmacy and Pharmacology 32: 471–477 (1980).

    Article  PubMed  Google Scholar 

  • Pollick, C.; Giacomini, K.M.; Blaschke, T.F.; Nelson, W.L.; Turner-Tamiyasu, K.; Briskin, V. and Popp, R.L.: The cardiac effects of d- and l-disopyramide in normal subjects: A non-invasive study. Circulation 66: 447–453 (1981).

    Article  Google Scholar 

  • Ranney, R.G.; Dean, R.R.; Karim, A. and Radzialowski, F.M.: Disopyramide phosphate: Pharmacokinetics and pharmacologie relationships of a new antiarrhythmic agent. Archives of International Pharmacodynamics and Therapeutics 191: 162–188 (1971).

    CAS  Google Scholar 

  • Valdivieso, L.H.; Giacomini, K.M. and Blaschke, T.F.: Disopyramide enantiomers bind stereoselectively to plasma proteins. Proceedings of the II World Conference of Clinical Pharmacology and Therapeutics (In press, 1983).

  • Ward, J.W. and Kinghorn, G.R.: The pharmacokinetics of disopyramide following myocardial infarction with special reference to oral and intravenous dose regimens. Journal of International Medical Research 4 (Suppl. 1): 49–53 (1976).

    PubMed  CAS  Google Scholar 

  • Whiting, B.; Holford, N.H.G. and Sheiner, L.B.: Quantitative analysis of the disopyramide concentration-effect relationship. British Journal of Clinical Pharmacology 9: 67–75 (1980).

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacy, University of California, San Francisco, California, 94143, USA

    Kathleen M. Giacomini & Terrence F. Blaschke

  2. Department of Medicine, Stanford University Medical Center, Stanford, California, USA

    Kathleen M. Giacomini & Terrence F. Blaschke

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  1. Kathleen M. Giacomini
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  2. Terrence F. Blaschke
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Giacomini, K.M., Blaschke, T.F. Effect of Concentration-Dependent Binding to Plasma Proteins on the Pharmacokinetics and Pharmacodynamics of Disopyramide. Clin Pharmacokinet 9 (Suppl 1), 42–48 (1984). https://doi.org/10.2165/00003088-198400091-00006

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  • DOI: https://doi.org/10.2165/00003088-198400091-00006

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