Factors Affecting Quinidine Protein Binding in Humans

Abstract

The free (unbound) concentration of drug in plasma is often an important determinant of pharmacological and toxicological effects. Unfortunately, studies examining the factors influencing the free fraction of quinidine in plasma have yielded inconsistent results. It is probable that differences in the type of blood collection tubes utilized and the analytical procedure employed biased some of these estimates of quinidine binding. The present study was executed in a manner free of factors now known to introduce artifacts into estimates of the free fraction of quinidine. In healthy volunteers, the free fraction of quinidine (1.0 μg/mL) was 0.129 ± 0.019 (mean ± SD) and was constant throughout the therapeutic range. A high-affinity, low-capacity binding site (K = 1.17 × 105 M−1; nP = 3.49 × 10−5 M) and a low-affinity, high-capacity binding site (K = 1.33 × 103 M−1; nP = 3.14 × 10−3 M) were identified. The characteristics of quinidine binding in a 4.5-g/dL solution of human serum albumin (K = 3.05 × 103 M−1; nP = 1.36 × 10−3 M) suggested that the low-affinity, high-capacity binding site was on this protein. In the presence of tris(butoxyethyl) phosphate (75 μg/mL), the quinidine free fraction increased from 0.114 to 0.231. A lidocaine concentration of 250 μg/mL caused a similar increase. Patients suffering traumatic injury had a significant increase in α1-acid glycoprotein concentration (197 mg/dL) and a decreased quinidine free fraction (0.075 ± 0.019). Patients with hyperlipidemia had free fractions similar to those observed in healthy individuals (0.118 ± 0.019). These data suggest that the high-affinity, low-capacity binding site is on α1-acid glycoprotein and that lipoproteins are of little importance in the protein binding of quinidine.