Decreased binding of verapamil to plasma proteins in patients with liver disease.

The binding of verapamil to proteins in plasma of patients with liver disease was studied using equilibrium dialysis. Compared with an age- and sex-matched control group, the fraction unbound of verapamil was significantly greater in patients with liver disease (p less than 0.01). The mean +/- SD fraction unbound in the patients was 0.16 +/- 0.05 compared with 0.099 +/- 0.015 in the control group (p less than 0.01). The higher fraction unbound in the liver disease patients appeared to be largely due to lower concentrations of binding proteins in plasma. A substantial effect of pH on the binding of verapamil to plasma proteins was observed. The increase in fraction unbound is consistent with previous findings of an increased apparent volume of distribution in patients with liver disease. Because of the pharmacokinetic characteristics of verapamil, the observed altered binding to plasma proteins would be expected to result in higher steady-state plasma concentrations of unbound drug after intravenous but not oral administration. For clinical monitoring, at any given total concentration, the unbound concentration would be approximately 60% higher in patients with liver disease. This study, together with previous studies in the literature, suggests that caution should be exercised in the administration of verapamil to patients with liver disease.