Klouček Anežka, Šmardová Jaroslava, Sklenárová Michaela, Dvořáková Alexandra, Chalupský Karel, Ryšánek Pavel, Odložilíková Martina Nora, Bartůněk Aleš, Perlík Vít, Mertlíková-Kaiserová Helena, Michálek Pavel, Šíma Martin, Slanař Ondřej
Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Ann Med. 2025 Dec;57(1):2534523. doi: 10.1080/07853890.2025.2534523. Epub 2025 Jul 20.
The aim of this study was to evaluate the pharmacokinetics and lung penetration of zanamivir in healthy rats and rats with lipopolysaccharide (LPS)-induced acute lung injury (ALI).
Three pharmacokinetic (PK) studies have been conducted to evaluate systemic PK and local exposure of zanamivir in male Wistar rats ( = 62, 16 weeks old). Zanamivir was administered to healthy rats and rats with LPS-induced ALI intravenously (IV) and by inhalation (INH) nebulisation. Serum and bronchoalveolar lavage (BAL) fluid concentrations were analysed to assess drug permeation across barriers. All zanamivir concentrations were determined using the HPLC-MS/MS method.
The concentrations of zanamivir in BAL after IV dosing were approximately 3.1-, 4.0- and 5.0-fold higher in healthy animals compared with ALI at 30, 60 and 240 min after dosing, respectively ( = 0.005, 0.001 and 0.016). Zanamivir permeation between BAL fluid and serum was compared for IV and INH administrations, revealing that the BAL AUC following IV administration was 6.5-fold lower than after INH. Furthermore, the AUC in BAL fluid after IV administration was approximately 3.3 times higher in healthy animals than those with ALI (35,815 vs. 10,886 ng/mL × h). ALI also reduced the rate and extent of systemic absorption compared to healthy conditions. The absolute bioavailability of nebulised zanamivir was 1.91%.
Our findings confirm PK superiority of INH administration to achieve local intrapulmonary exposition and indicate that ALI significantly impairs zanamivir penetration into the lungs from systemic circulation.
本研究旨在评估扎那米韦在健康大鼠和脂多糖（LPS）诱导的急性肺损伤（ALI）大鼠中的药代动力学及肺部渗透情况。
进行了三项药代动力学（PK）研究，以评估扎那米韦在雄性Wistar大鼠（n = 62，16周龄）中的全身PK及局部暴露情况。将扎那米韦通过静脉注射（IV）和雾化吸入（INH）给药于健康大鼠和LPS诱导的ALI大鼠。分析血清和支气管肺泡灌洗（BAL）液浓度以评估药物跨屏障渗透情况。所有扎那米韦浓度均采用HPLC-MS/MS法测定。
静脉给药后，在给药后30、60和240分钟时，健康动物BAL中扎那米韦浓度分别比ALI动物高约3.1倍、4.0倍和5.0倍（P = 0.005、0.001和0.016）。比较了IV和INH给药时BAL液与血清之间的扎那米韦渗透情况，结果显示IV给药后BAL的AUC比INH给药后低6.5倍。此外，IV给药后健康动物BAL液中的AUC比ALI动物高约3.3倍（35,815 vs. 10,886 ng/mL×h）。与健康状态相比，ALI也降低了全身吸收的速率和程度。雾化扎那米韦的绝对生物利用度为1.91%。
我们的研究结果证实了INH给药在实现局部肺内暴露方面的PK优势，并表明ALI显著损害扎那米韦从体循环进入肺部的渗透。
