Effects of quinidine, verapamil and nifedipine on the pharmacokinetics and pharmacodynamics of digitoxin during steady state conditions.

In a prospective clinical study the effects of quinidine (Q), verapamil (V) and nifedipine (N) on the pharmacokinetics and pharmacodynamics of digitoxin (DGT) were studied in 28 subjects achieving steady state conditions. DGT plasma concentration increased continuously up to a new steady state level after 3 to 4 weeks of Q or V coadministration. Mean steady state DGT concentrations were 45% and 27%, respectively, higher than during treatment with DGT alone. Renal DGT clearance and endogeneous creatine clearance were not significantly affected by Q or V coadministration, while nonrenal DGT clearance was significantly reduced by an average of 40.5% and 29%, respectively. Similarly, elimination half-life determined in 4 volunteers once in presence and once in absence of Q was prolonged by 34.5%. The increased plasma DGT concentration seems to be pharmacodynamically active as demonstrated by electrographic measures and systolic time intervals. While the antagonistic effects of Q and V on QT-duration and myocardial performance with increasing DGT plasma levels nearly disappeared, the synergistic effects of DGT and Q or V were continuously intensified. In contrast, N had no clinically significant effect on pharmacokinetics and pharmacodynamics of DGT. From these investigations it could be concluded that Q and V had a clinically significant effect on pharmacokinetics and pharmacodynamics of DGT but to a lesser extent and, at least in part, by different mechanism than shown for digoxin.