PHARMACOKINETIC AND CLINICAL IMPLICATIONS OF QUINIDINE PROTEIN-BINDING

Equilibrium dialysis was used to assess factors influencing quinidine binding to serum proteins. Binding was not influenced by prolonged storage at −20° or by variation in total serum quinidine concentrations over a clinically relevant range. Protein binding decreased with increasing temperature between 24 and 37° (p < 0.001) and when total serum protein concentrations were decreased from 6.0 to 2.6 g/100 ml by dilution with phosphate buffer. The addition of therapeutic concentrations of salicylic acid, phenylbutazone, and tolbutamide significantly reduced quinidine binding (p < 0.025), but 10 other commonly coadministered drugs did not. Displacement of quinidine by salicylic acid was nonlinear; the extent of displacement increased with increasing total quinidine concentrations. The unbound quinidine fraction among 12 healthy subjects varied almost twofold and was partly explained by differences in serum albumin concentrations within the usual range of normal (3.9–4.8 g/100 ml). Pharmacokinetic analysis was performed on simultaneous total and unbound serum quinidine concentrations in 12 volunteers who received single intravenous doses of quinidine lactate. The mean elimination half‐lives of total and unbound quinidine were not significantly different. However, the mean volume of distribution and total metabolic clearance of unbound quinidine were considerably greater than those determined using total drug concentrations. Renal clearance of free quinidine exceeded creatinine clearance, consistent with tubular secretion of the unbound fraction. Between‐subject variability in elimination half‐life and metabolic clearance of quinidine was less when free rather than total serum concentrations were analyzed. Acute ECG changes due to intravenous quinidine correlated better with unbound than with total drug concentrations. Thus, measurement of unbound as well as total serum quinidine concentrations may provide additional understanding of variations between individuals in pharmacokinetics and clinical effects of quinidine. Copyright © 1979 Wiley‐Liss, Inc., A Wiley Company