Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Quinidine pharmacokinetics in man: Choice of a disposition model and absolute bioavailability studies

Abstract

Parameters describing disposition and absolute oral bioavailability of quinidine were determined in ten normal male volunteers using a specific assay. Various models were compared for their ability to describe the experimental data. An intravenous quinidine gluconate and an oral quinidine sulfate solution were administered (3.74 mg/kg quinidine base). In three subjects the intravenous and oral studies were repeated. One-, two-, and three-compartment models with zeroand first-order input were fitted to the plasma concentrations. The selection of the best model was made by the Akaike information criterion and by eye. After intravenous administration, plasma concentrationtime curves could be adequately described by a twocompartment model. Mean disposition constants (±SD) were obtained from individualized fits (V1: 0.398 ±0.336 liter/kg, Vdarea: 2.53±0.72 liter/kg, α: 0.316±0.294 min−1, Β: 0.00204 ± 0.00262 min1, k2: 0.0305 ±0.010 min−1). A clearance of 4.9 ±1.5 ml/min/kg was observed. After oral administration, threecompartment models were needed to describe the observed data in some cases. Absorption was in most cases best described by a zeroorder rather than by a firstorder process. The time to peak concentration varied from 23 to 121 min, the lag time was always less than 3 min, and the mean elimination rate constant was 0.00171 min−1. The mean oral bioavailability of quinidine was 0.70 ±0.17.

This is a preview of subscription content, log in to check access.

References

  1. 1.

    M. Sokolow and A. L. Edgar. Blood quinidine concentrations as a guide in the treatment of cardiac arrhythmias.Circulation 1:576–592 (1950).

  2. 2.

    M. Sokolow and R. E. Ball. Factors influencing conversion of chronic atrial fibrillation with special reference to serum quinidine concentration.Circulation 14:568–583 (1956).

  3. 3.

    K. M. Kessler, D. T. Lowenthal, H. Warner, T. Gibson, W. Briggs, and M. M. Reidenberg. Quinidine elimination in patients with congestive heart failure or poor renal function.New Eng. J. Med. 290:706–709 (1974).

  4. 4.

    E. Ditlefsen. Concentrations of quinidine in blood following oral, parenteral and rectal administration.Acta Med. Scand. 146:81–92 (1953).

  5. 5.

    E. P. Hiatt. Plasma concentrations following the oral administration of single doses of the principal alkaloids of cinchona bark.J. Pharmacol. Exp. Ther. 81:160–163 (1944).

  6. 6.

    H. Zettner and D. Michel. Blutspiegeluntersuchungen zur Frage der zweckmaessigsten Applikationsform bei Chinidindauertherapie.Klin. Wschr. 49:575–578 (1971).

  7. 7.

    S. Riegelman. Physiological and pharmacokinetic complexities in bioavailability testing.Pharmacology 8:118–141 (1972).

  8. 8.

    C. T. Ueda, B. J. Williamson, and B. S. Dzindzio. Absolute quinidine bioavailability.Clin. Pharmacol. Ther. 20:260–265 (1976).

  9. 9.

    K. A. Conrad, B. L. Molk, and C. A. Chidsey. Pharmacokinetic studies of quinidine in patients with arrhythmias.Circulation 55:1–7 (1977).

  10. 10.

    D. J. Greenblatt, H. J. Pfeifer, H. R. Ochs, K. Franke, D. S. McLaughlin, T. W. Smith, and J. Koch-Weser. Pharmacokinetics of quinidine in humans after intravenous, intramuscular and oral administration.J. Pharmacol. Exp. Ther. 202:365–378 (1977).

  11. 11.

    N. H. G. Holford, S. Vozeh, P. Coates, J. R. Poweli, Jr., J. F. Thiercelin, and R. A. Upton. More on heparin lock.New Engl. J. Med. 296:1300–1301 (1977).

  12. 12.

    T. W. Guentert, P. E. Coates, R. A. Upton, D. L. Combs, and S. Riegelman. Determination of quinidine and its major metabolites by highperformance liquid chroma-toraphy.J. Chromatogr. 162:59–70 (1979).

  13. 13.

    K. C. Yeh and K. C. Kwan. A comparison of numerical integrating algorithms by trapezoidal, Lagrange and spline approximation.J. Pharmacokin. Biopharm. 6:79–98 (1978).

  14. 14.

    DRUGFUN, available through the “PROPHET”-System, U.S. National Institutes of Health; seeNatl. Comput. Conf. Exposition Proc. 43:457–468 (1974).

  15. 15.

    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).

  16. 16.

    H. Akaike. A new look at the statistical model identification.IEEE Tr. Automat. Contr. 19:716–723 (1973).

  17. 17.

    H. Akaike. An information criterion (AIC).Math. Sci. 14:5–9 (1976).

  18. 18.

    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).

  19. 19.

    A. B. Houston and W. F. Perry. The plasma concentration of quinidine after oral administration and its effects on auricular fibrillation.Can. Med. Assoc. J. 63:56–60 (1950).

  20. 20.

    J. G. Wagner,Fundamentals of Clinical Pharmacokinetics, 1st ed., Drug Intelligence Publications, Hamilton, Ill., 1975, p. 347.

  21. 21.

    J. C. K. Loo and S. Riegelman. New method for calculating the intrinsic absorption rate of drugs.J. Pharm. Sci. 57:918–928 (1968).

  22. 22.

    P. Bolme and U. Otto. Dose-dependence of the pharmacokinetics of quinidine.Eur. J. Pharmacol. 12:73–76 (1977).

  23. 23.

    C. T. Ueda, D. S. Hirschfeld, M. M. Scheinman, M. Rowland, B. J. Williamson, and B. S. Dzindzio. Disposition kinetics of quinidine.Clin. Pharmacol. Ther. 19(1):30–36 (1976).

  24. 24.

    C. T. Ueda and B. S. Dzindzio. Quinidine kinetics in congestive heart failure.Clin. Pharmacol. Ther. 23:158–164 (1978).

  25. 25.

    H. G. Boxenbaum, S. Riegelman, and R. M. Elashoff. Statistical estimations in phar-macokinetics.J. Pharmacokin. Biopharm. 2:123–148 (1974).

  26. 26.

    S. S. Wilks.Mathematical Statistics, Wiley, New York, 1962, p. 408ff.

Download references

Author information

Correspondence to Sidney Riegelman.

Additional information

This study was supported by funds from Food and Drug Administration Contract No. 223-74-3145. T. W. G. acknowledges support from the Swiss National Science Foundation, N. H. G. H. received a NIH fellowship for training in Clinical Pharmacology (GM 00001).

An erratum to this article is available at http://dx.doi.org/10.1007/BF01065195.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Guentert, T.W., Holford, N.H.G., Coafes, P.E. et al. Quinidine pharmacokinetics in man: Choice of a disposition model and absolute bioavailability studies. Journal of Pharmacokinetics and Biopharmaceutics 7, 315–330 (1979). https://doi.org/10.1007/BF01062532

Download citation

Key words

  • quinidine
  • pharmacokinetic models
  • curve fitting
  • bioavalability
  • absorption
  • humans
  • plasma
  • intravenous
  • oral