ITRACONAZOLE GREATLY INCREASES PLASMA-CONCENTRATIONS AND EFFECTS OF FELODIPINE

Background: Felodipine, a dihydropyridine calcium antagonist, is exten sively metabolized by CYP3A4. Itraconazole strongly interacts with som e of the substrates of CYP3A4 (e.g., terfenadine, triazolam and lovast atin); hence it is important to uncover the possible interaction of it raconazole with felodipine. Methods: A double-blind, randomized, two-p hase crossover design was used to investigate the interaction between felodipine and itraconazole. Nine healthy volunteers received either 2 00 mg itraconazole or placebo orally once a day for 4 days. On day 4, each ingested a single 5 mg oral dose of felodipine. Plasma concentrat ions of felodipine and itraconazole were determined and systolic and d iastolic blood pressures and heart rate were measured up to 32 hours. Results: On average, itraconazole increased the peak plasma concentrat ion (C-max) of felodipine nearly eightfold (p < 0.001), the areas unde r the felodipine concentration-time curve [AUC(0-32) and AUC(0-infinit y)] about sixfold (p < 0.001), and the elimination half-life twofold ( p < 0.05). In seven of the nine subjects, even the C-max of felodipine was lower without itraconazole than the 32-hour concentrations during the itraconazole phase. The decreases in blood pressure and the incre ases in heart rate were significantly greater during the itraconazole phase than during the placebo phase. Conclusions: Itraconazole greatly increases plasma concentrations and effects of oral felodipine. The i nhibition of CYP3A4 during the first-pass and elimination phases of fe lodipine seems to be the mechanism of the observed interaction. The co ncomitant use of itraconazole and some other azole antifungals with fe lodipine and other dihydropyridine calcium antagonists should be avoid ed or their doses should be reduced accordingly.