AUTHOR=Pozniak Jiří , Ryšánek Pavel , Smrčka David , Kozlík Petr , Křížek Tomáš , Šmardová Jaroslava , Nováková Anežka , Das Debanjan , Bobek Daniel , Arora Mahak , Hofmann Jiří , Doušová Tereza , Šíma Martin , Slanař Ondřej 

TITLE=Ivacaftor pharmacokinetics and lymphatic transport after enteral administration in rats

JOURNAL=Frontiers in Pharmacology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1331637

DOI=10.3389/fphar.2024.1331637

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> Ivacaftor is a modern drug used in the treatment of cystic fibrosis. It is highly lipophilic and exhibits a strong positive food effect. These characteristics can be potentially connected to a pronounced lymphatic transport after oral administration.</p><p><bold>Methods:</bold> A series of studies was conducted to describe the basic pharmacokinetic parameters of ivacaftor in jugular vein cannulated rats when dosed in two distinct formulations: an aqueous suspension and an oil solution. Additionally, an anesthetized mesenteric lymph duct cannulated rat model was studied to precisely assess the extent of lymphatic transport.</p><p><bold>Results:</bold> Mean ± SD ivacaftor oral bioavailability was 18.4 ± 3.2% and 16.2 ± 7.8%, respectively, when administered as an aqueous suspension and an oil solution. The relative contribution of the lymphatic transport to the overall bioavailability was 5.91 ± 1.61% and 4.35 ± 1.84%, respectively.</p><p><bold>Conclusion:</bold> Lymphatic transport plays only a minor role in the process of ivacaftor intestinal absorption, and other factors are, therefore, responsible for its pronounced positive food effect.</p>