Effect of concentration-dependent binding to plasma proteins on the pharmacokinetics and pharmacodynamics of disopyramide.
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.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D004206:Disopyramide / Q000097:blood / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008657:Metabolic Clearance Rate; D011817:Rabbits; D012709:Serum Albumin / Q000378:metabolism
D001798:Blood Proteins; D012709:Serum Albumin; D004206:Disopyramide