Abstract
Disopyramide has nonlinear protein binding and thus the relationship between the extent of its bioavailability and AUC,the area under the plasma concentration-time curve, is (1) nonlinear and (2) absorption rate-dependent. The unbound species follows linear pharmacokinetics. A solution of disopyramide, the innovator's product, and two generic formulations were found to be statistically indistinguishable in their bioavailability of disopyramide, whether comparison was based upon AUCor area under the plasma unbound concentration-time curve (AUCu).The AUCand AUCugave similar results because of truly similar bioavailability, coupled with sufficiently similar release rates, among the four preparations chosen for study. The concentration dependence of disopyramide protein binding and the time course of unbound plasma concentrations were fit by models which then allowed prediction of AUCunder various biopharmaceutical scenarios. Nonlinear binding of disopyramide to plasma proteins renders AUCan insensitive parameter for the discrimination of products with different extents of bioavailability; immediate release products allowing bioavailabilities of 75 or 125% relative to the solution can generate AUCs86 and 112%, respectively, of that from the solution. Nonlinear binding, furthermore, leads to a tendency for AUC tooverestimate the bioavailability of slower release products in single-dose studies; if AUCwere the index of bioavailability, products permitting the same bioavailability as the solution but releasing over 12 hr could appear to allow 114% relative bioavailability. Moreover, in some situations the bias arising from the insensitivity of AUCto product differences can be reinforced by the dependence of AUCon release rate; an apparent relative bioavailability of 80% can be achieved by a 12-hr release product allowing a true relative bioavailability of a mere 58%. While multiple-dose studies appear largely to avoid the tendency to overestimate low bioavailability in slow-release products, in these studies AUCappears to be even more insensitive in resolving discrepancies between products. Assay technology now available makes AUCua feasible and more reliable index of bioavailability than AUCwhen plasma protein binding of drugs is nonlinear.
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References
P. H. Hinderling, J. Bres, and E. R. Garrett. Protein binding and erythrocyte partitioning of disopyramide and its monodealkylated metabolite.J. Pharm. Sci. 63:1684–1690 (1974).
P. H. Hindeling and E. R. Garrett. Pharmacokinetics of the antiarrhythmic disopyramide in healthy humans.J. Pharmacokin. Biopharm. 4:199–230 (1976).
K. M. Giacomini, S. E. Swezey, K. Turner-Tamiyasu, and T. F. Blaschke. The effect of saturable binding to plasma proteins on the pharmacokinetic properties of disopyramide.J. Pharmacokin. Biopharm. 10:1–14 (1982).
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).
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).
Metropolitan Life Insurance Bulletin. Metropolitan Life Insurance Company, New York, November–December 1959.
D. B. Haughey and J. J. Lima. The influence of blood collection technique on serum and plasma protein binding of disopyramide.Eur. J. Clin. Pharmacol. 22:185–189 (1982).
M. M. Bradford. A rapid sensitive method for quantification of microgram quantities of protein.Anal. Biochem. 72:248–257 (1976).
EMIT Disopyramide Assay. Syva Co., Palo Alto, California, 1980.
B. E. Pape. Enzyme immunoassay of disopyramide in serum.Clin. Chem. 27:2038–2040 (1981).
W. L. Chiou. Critical evaluation of the potential error in pharmacokinetic studies of using the linear trapezoidal rule method for the calculation of the area under the plasma level time curve.J. Pharmacokin. Biopharm. 6:539–546 (1978).
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).
M. Thibonnier, N. H. G. Holford, R. A. Upton, C. D. Blume, and R. L. Williams. Pharmacokinetic-pharmacodynamic analysis of unbound disopyramide directly measured in serial plasma samples in man.J. Pharmacokin. Biopharm. 12:559–573 (1984).
D. K. Dubetz, N. N. Brown, W. D. Hooper, M. J. Eadie, and J. H. Tyrer. Disopyramide pharmacokinetics and bioavailability.Br. J. Clin. Pharmacol. 6:279–281 (1978).
A. Karim, E. N. Schubert, T. S. Burns, M. Palmer, and M. A. Zinny. Disopyramide plasma concentrations following single and multiple doses of the immediate-and controlled-release capsules.Angiology 34:375–392 (1983).
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).
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Upton, R.A., Williams, R.L. The impact of neglecting nonlinear plasma-protein binding on disopyramide bioavailability studies. Journal of Pharmacokinetics and Biopharmaceutics 14, 365–379 (1986). https://doi.org/10.1007/BF01059197
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DOI: https://doi.org/10.1007/BF01059197