title: Uptake and efflux kinetics, and intracellular activity of voriconazole against Aspergillus fumigatus in human pulmonary epithelial cells: a new application for the prophylaxis and early treatment of invasive pulmonary aspergillosis.
abstract: Invasive pulmonary aspergillosis (IPA), most caused by Aspergillus fumigatus, is a serious life-threatening infection in immunocompromised patients. Voriconazole is used to prevent and treat IPA. However, little is known about the pharmacological characteristics of voriconazole in pulmonary epithelial cells, which are the target site for the prophylaxis and early treatment of IPA. The aim of the study was to evaluate the kinetics and activity of voriconazole against A. fumigatus in A549 cells. High-performance liquid chromatography/tandem mass spectrometry and time-kill method were used to study the cellular pharmacokinetic and pharmacodynamics of voriconazole. Voriconazole exerted a concentration-dependent toxic effect on A549 cells and could penetrate into cells, reaching plateau concentrations of 1.14 ± 0.64, 3.72 ± 1.38 and 6.36 ± 0.95 ng/mg protein after A549 cells were exposed to voriconazole at extracellular concentrations of 2, 8 and 16 mg/L for 2 h, respectively. The efflux of voriconazole was rapid, with a half-life of 10.2 min. Voriconazole can decrease the A. fumigatus conidia invade cells, and the number of viable A. fumigatus conidia in cells can be decreased 2.1- to 20.6-fold when A549 cells were cultured in medium containing voriconazole. After 24-h incubation, 75.6% and 80.5% of intracellular A. fumigatus were killed when extracellular voriconazole concentration was 8 and 16 mg/L, respectively. This study illustrated a new application for the prophylaxis and early treatment of IPA from the cellular pharmacokinetics and pharmacodynamics and emphasized the importance of monitoring concentrations of voriconazole in epithelial lining fluid in immunocompromised patients receiving voriconazole therapy.
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
authors.forename: Taotao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
authors.forename: Qianting
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
authors.forename: Ti
authors.initials: T
authors.lastname: Meng
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Laboratory, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
authors.forename: Jin'e
authors.initials: J
authors.lastname: Lei
authors.affiliation: School of Pharmacy, Xi'an Jiaotong University, Xi'an, 710061, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xing
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
authors.forename: Yalin
authors.initials: Y
authors.lastname: Dong
mesh_terms: D000072283:A549 Cells; D019072:Antibiotic Prophylaxis / Q000379:methods; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001232:Aspergillus fumigatus / Q000187:drug effects*; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000187:drug effects* / Q000382:microbiology; D006207:Half-Life; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis / Q000188:drug therapy* / Q000382:microbiology; D007700:Kinetics; D008168:Lung / Q000187:drug effects* / Q000382:microbiology; D065819:Voriconazole / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D065819:Voriconazole
keywords: Aspergillus fumigatus; kinetics; nystatin assay; pulmonary epithelial cells; voriconazole