Itraconazole greatly increases plasma concentrations and effects of felodipine.
BACKGROUND
Felodipine, a dihydropyridine calcium antagonist, is extensively metabolized by CYP3A4. Itraconazole strongly interacts with some of the substrates of CYP3A4 (e.g., terfenadine, triazolam and lovastatin); hence it is important to uncover the possible interaction of itraconazole with felodipine.


METHODS
A double-blind, randomized, two-phase crossover design was used to investigate the interaction between felodipine and itraconazole. Nine healthy volunteers received either 200 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 concentrations of felodipine and itraconazole were determined and systolic and diastolic blood pressures and heart rate were measured up to 32 hours.


RESULTS
On average, itraconazole increased the peak plasma concentration (Cmax) of felodipine nearly eightfold (p < 0.001), the areas under the felodipine concentration-time curve [AUC(0-32) and AUC(0-infinity)] about sixfold (p < 0.001), and the elimination half-life twofold (p < 0.05). In seven of the nine subjects, even the Cmax of felodipine was lower without itraconazole than the 32-hour concentrations during the itraconazole phase. The decreases in blood pressure and the increases 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 inhibition of CYP3A4 during the first-pass and elimination phases of felodipine seems to be the mechanism of the observed interaction. The concomitant use of itraconazole and some other azole antifungals with felodipine and other dihydropyridine calcium antagonists should be avoided or their doses should be reduced accordingly.
Jalava
K M
KM
Department of Clinical Pharmacology, University of Helsinki, Finland.
Olkkola
K T
KT
Neuvonen
P J
PJ
D000328:Adult; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D002121:Calcium Channel Blockers / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004357:Drug Synergism; D015736:Felodipine / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D017964:Itraconazole / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D012016:Reference Values
D000935:Antifungal Agents; D002121:Calcium Channel Blockers; D017964:Itraconazole; D015736:Felodipine