Itraconazole increases plasma concentrations of quinidine

Quinidine is eliminated mainly by CYP3A4-mediated metabolism. Itraconazole interacts with some but not all of the substrates of CYP3A4; it is therefore important to study the possible interaction of itraconazole with quinidine.

A double-blind, randomized, two-phase crossover study design was used with nine healthy volunteers. Itraconazole (200 mg) or placebo was ingested once a day for 4 days. A single 100 mg oral dose of quinidine sulfate was ingested on day 4. Plasma concentrations of quinidine, itraconazole, and hydroxyitraconazole, as well as cumulative excretion of quinidine into urine, were determined up to 24 hours. The ECG, heart rate, and blood pressure were also recorded up to 24 hours.

On average the peak plasma concentration of quinidine increased to 1.6-fold (p < 0.05), and the area under the concentration-time curve of quinidine increased to 2.4-fold (p < 0.01) by itraconazole. The elimination half-life of quinidine was prolonged 1.6-fold (p < 0.001), and the area under the 3-hydroxyquinidine/quinidine ratio-time curve decreased to one-fifth (p < 0.001) by itraconazole. The renal clearance of quinidine decreased 50% (p < 0.001) by itraconazole, whereas the creatinine clearance was unaffected. The QTc interval correlated with the concentrations of quinidine during both itraconazole and placebo phases (r2 = 0.71 and r2 = 0.79, respectively; p < 0.01), although only minor changes between the phases were observed in other pharmacodynamic variables.

Itraconazole increases plasma concentrations of oral quinidine, probably by inhibiting the CYP3A4 isozyme during the first-pass and elimination phases of quinidine. The decreased renal clearance of quinidine might be the result of the inhibition of P-glycoprotein-mediated tubular secretion of quinidine by itraconazole. The concentrations of quinidine should be closely monitored if itraconazole or some other potent CYP3A inhibitors are used with quinidine.