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Itraconazole, a P‐Glycoprotein and CYP3A4 Inhibitor, Markedly Raises the Plasma Concentrations and Enhances the Renin‐Inhibiting Effect of Aliskiren
Author(s) -
Tapaninen Tuija,
Backman Janne T.,
Kurkinen Kaisa J.,
Neuvonen Pertti J.,
Niemi Mikko
Publication year - 2011
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270010365885
Subject(s) - aliskiren , itraconazole , renin inhibitor , pharmacology , pharmacokinetics , plasma renin activity , chemistry , cyp3a4 , crossover study , endocrinology , renin–angiotensin system , ketoconazole , placebo , medicine , metabolism , blood pressure , antifungal , alternative medicine , cytochrome p450 , dermatology , pathology
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.