title: In vitro study of the variable effects of proton pump inhibitors on voriconazole.
abstract: Voriconazole is a broad-spectrum antifungal agent used for the treatment of severe fungal infections. Maintaining therapeutic concentrations of 1 to 5.5 μg/ml is currently recommended to maximize the exposure-response relationship of voriconazole. However, this is challenging, given the highly variable pharmacokinetics of the drug, which includes metabolism by cytochrome P450 (CYP450) isotypes CYP2C19, CYP3A4, and CYP2C9, through which common metabolic pathways for many medications take place and which are also expressed in different isoforms with various metabolic efficacies. Proton pump inhibitors (PPIs) are also metabolized through these enzymes, making them competitive inhibitors of voriconazole metabolism, and coadministration with voriconazole has been reported to increase total voriconazole exposure. We examined the effects of five PPIs (rabeprazole, pantoprazole, lansoprazole, omeprazole, and esomeprazole) on voriconazole concentrations using four sets of human liver microsomes (HLMs) of different CYP450 phenotypes. Overall, the use of voriconazole in combination with any PPI led to a significantly higher voriconazole yield compared to that achieved with voriconazole alone in both pooled HLMs (77% versus 59%; P < 0.001) and individual HLMs (86% versus 76%; P < 0.001). The mean percent change in the voriconazole yield from that at the baseline after PPI exposure in pooled microsomes ranged from 22% with pantoprazole to 51% with esomeprazole. Future studies are warranted to confirm whether and how the deliberate coadministration of voriconazole and PPIs can be used to boost voriconazole levels in patients with difficult-to-treat fungal infections.
authors.affiliation: Department of Extremity Trauma and Regenerative Medicine, United States Army Institute of Surgical Research, JBSA Ft. Sam Houston, Texas, USA.
authors.forename: Krista L
authors.initials: KL
authors.lastname: Niece
authors.affiliation: College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA Pharmacotherapy Education and Research Center, The University of Texas Health Sciences Center, San Antonio, Texas, USA.
authors.forename: Natalie K
authors.initials: NK
authors.lastname: Boyd
authors.affiliation: Department of Extremity Trauma and Regenerative Medicine, United States Army Institute of Surgical Research, JBSA Ft. Sam Houston, Texas, USA Infectious Disease Service, Department of Medicine, San Antonio Military Medical Center, JBSA Ft. Sam Houston, Texas, USA kevin.s.akers.mil@mail.mil.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Akers
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000737:chemistry; D000935:Antifungal Agents / Q000737:chemistry; D065731:Cytochrome P-450 CYP2C19 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D004347:Drug Interactions; D064098:Esomeprazole / Q000737:chemistry; D006801:Humans; D064747:Lansoprazole / Q000737:chemistry; D008862:Microsomes, Liver / Q000378:metabolism; D009853:Omeprazole / Q000737:chemistry; D000077402:Pantoprazole; D054328:Proton Pump Inhibitors / Q000737:chemistry*; D064750:Rabeprazole / Q000737:chemistry; D065819:Voriconazole / Q000737:chemistry*
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000935:Antifungal Agents; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D064750:Rabeprazole; D003577:Cytochrome P-450 Enzyme System; D000077402:Pantoprazole; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole; D009853:Omeprazole; D064098:Esomeprazole