ITRACONAZOLE INCREASES PLASMA-CONCENTRATIONS OF QUINIDINE

Background: Quinidine is eliminated mainly by CPP3A4-mediated metaboli sm. 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. Methods: A double-blind, randomized, two -phase crossover study design was used with nine healthy volunteers. I traconazole (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. Pl asma concentrations of quinidine, itraconazole, and hydroxyitraconazol e, as well as cumulative excretion of quinidine into urine, were deter mined up to 24 hours. The EGG, heart rate, and blood pressure were als o recorded up to 24 hours. Results: On average the peak plasma concent ration of quinidine increased to 1.6-fold (p < 0.05), and the area und er the concentration-time curve of quinidine increased to 2.4-fold (p < 0.01) by itraconazole. The elimination half-life of quinidine was pr olonged 1.6-fold (p < 0.001), and the area under the 3-hydroxyquinidin e/quinidine ratio-time curve decreased to one-fifth (p < 0.001) by itr aconazole. The renal clearance of quinidine decreased 50% (p < 0.001) by itraconazole, whereas the creatinine clearance was unaffected. The QT, interval correlated with the concentrations of quinidine during bo th itraconazole and placebo phases (r(2) = 0.71 and r(2) = 0.79, respe ctively; p < 0.01), although only minor changes between the phases wer e observed in other pharmacodynamic variables. Conclusions: Itraconazo le increases plasma concentrations of oral quinidine, probably by inhi biting 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 inhibi tors are used with quinidine.