title: Itraconazole, a P-glycoprotein and CYP3A4 inhibitor, markedly raises the plasma concentrations and enhances the renin-inhibiting effect of aliskiren.
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.
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, FI-00029 HUS, Finland.
authors.forename: Tuija
authors.initials: T
authors.lastname: Tapaninen
authors.forename: Janne T
authors.initials: JT
authors.lastname: Backman
authors.forename: Kaisa J
authors.initials: KJ
authors.lastname: Kurkinen
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: Mikko
authors.initials: M
authors.lastname: Niemi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000328:Adult; D000577:Amides / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000652:urine; D000935:Antifungal Agents / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000652:urine; D001711:Biotransformation / Q000187:drug effects; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000652:urine; D005260:Female; D005650:Fumarates / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000652:urine; D006207:Half-Life; D006801:Humans; D017964:Itraconazole / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008657:Metabolic Clearance Rate; D012083:Renin / Q000097:blood; D055815:Young Adult; D000092502:Renin Inhibitors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000577:Amides; D000935:Antifungal Agents; D000959:Antihypertensive Agents; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D005650:Fumarates; D017964:Itraconazole; D012083:Renin; D000092502:Renin Inhibitors; C084794:hydroxyitraconazole; C446481:aliskiren; C510163:CYP3A4 protein, human