Abstract
In a randomized crossover study, 11 healthy volunteers took 100 mg (first dose 200 mg) of the antifungal drug itraconazole, a P-glycoprotein and CYP3A4 inhibitor, or placebo twice daily for 5 days. On day 3, they ingested a single 150-mg dose of aliskiren, a renin inhibitor used in the treatment of hypertension. Itraconazole raised the peak plasma aliskiren concentration 5.8-fold (range, 1.1- to 24.3-fold; P < .001) and the area under the plasma aliskiren concentration-time curve 6.5-fold (range, 2.6- to 20.5-fold; P < .001) but had no significant effect on aliskiren elimination half-life. Itraconazole increased the amount of aliskiren excreted into the urine during 12 hours 8.0-fold (P < .001) and its renal clearance 1.2-fold (P = .042). Plasma renin activity 24 hours after aliskiren intake was 68% lower during the itraconazole phase than during the placebo phase (P = .011). In conclusion, itraconazole markedly raises the plasma concentrations and enhances the renin-inhibiting effect of aliskiren. The interaction is probably mainly explained by inhibition of the P-glycoprotein-mediated efflux of aliskiren in the small intestine, with a minor contribution from inhibition of CYP3A4. Concomitant use of aliskiren and itraconazole is best avoided.
Publication types
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Clinical Trial
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Randomized Controlled Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
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Adult
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Amides / blood
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Amides / pharmacokinetics*
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Amides / pharmacology
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Amides / urine
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Antifungal Agents / pharmacology*
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Antihypertensive Agents / blood
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Antihypertensive Agents / pharmacokinetics*
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Antihypertensive Agents / pharmacology
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Antihypertensive Agents / urine
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Biotransformation / drug effects
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Cross-Over Studies
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Cytochrome P-450 CYP3A
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Cytochrome P-450 CYP3A Inhibitors*
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Drug Interactions
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Enzyme Inhibitors / blood
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / urine
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Female
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Fumarates / blood
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Fumarates / pharmacokinetics*
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Fumarates / pharmacology
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Fumarates / urine
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Half-Life
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Humans
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Itraconazole / analogs & derivatives
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Itraconazole / blood
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Itraconazole / pharmacology*
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Male
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Metabolic Clearance Rate
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Renin / antagonists & inhibitors*
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Renin / blood
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Young Adult
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Amides
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Antifungal Agents
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Antihypertensive Agents
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Cytochrome P-450 CYP3A Inhibitors
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Enzyme Inhibitors
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Fumarates
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hydroxyitraconazole
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Itraconazole
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aliskiren
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human
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Renin