CONCENTRATION-DEPENDENCE OF DISOPYRAMIDE BINDING TO PLASMA-PROTEIN AND ITS INFLUENCE ON KINETICS AND DYNAMICS

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  • 1 January 1981
    • journal article
    • research article
    • Vol. 219  (3) , 741-747
Abstract
Disopyramide, an antiarrhythmic drug, binds to 2 independent sites on protein in human plasma. The 1st binding site located on .alpha.-1-acid glycoprotein has an association and a capacity constant of 1.0 .times. 106 M-1 and 3.5 .times. 10-6 M, respectively, and accounts for the majority of disopyramide binding. The 2nd site is probably located on albumin and accounts for 5-10% of the binding. The bound fraction of disopyramide was concentration-dependent at drug concentrations reported to be therapeutic. After administration of 100, 150, 200 and 300 mg doses of disopyramide (Norpace) to each of 4 human volunteers, the area under the free (unbound) disopyramide serum-concentration time curve averaged 2.32, 3.33, 5.21 and 8.24 mg/l .cntdot. h, respectively, and was directly proportional to dose. The elimination half-lives based on free and total drug concentrations averaged 4.36 and 6.51 h, respectively (P < 0.001), and were dose-independent. The peak response (change in pre-ejection period) and area under the response time curves were better related to free than to total serum concentrations of disopyramide.