The effect of quantitative structural properties of drugs on the extent of lymphatic transport is not well understood. Our study aimed to describe these principles in four cannabinoids, cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), and cannabinol (CBN) administered as oil solutions and nanoemulsions. A series of studies in jugular vein cannulated rats and anesthetized mesenteric lymph duct cannulated rats was conducted to measure drug oral bioavailability and lymphatic transport. Log P was measured, and quantitative structural properties were correlated to the extent of lymphatic absorption. Nanoemulsion did not increase the absolute bioavailability via lymph in CBD but led to an 8-fold increase in CBG and a 3-fold increase in CBC and CBN. There was an even higher increase in the absolute bioavailability via portal vein (11-fold for CBD, 71-fold for CBG, 8-fold for CBC, and 13-fold for CBN). Relative bioavailability via lymph increased with decreasing smallest orthogonal molecular size and topological polar surface area. Nanoemulsion did not affect the total oral bioavailability but led to an increased absorption into portal blood. Intestinal lymphatic transport plays a major role in the absorption of CBD, CBG, CBC, and CBN. Planarity of the molecule and low surface polarity could be crucial structural features facilitating lymphatic transport.

• Keywords
• cannabinoids, lymph-targeting, lymphatic transport, nanoemulsion, oral bioavailability, pharmacokinetics, quantitative structure−activity relationship (QSAR),
• MeSH
• Administration, Oral MeSH
• Biological Availability MeSH
• Biological Transport MeSH
• Emulsions chemistry   MeSH
• Cannabidiol chemistry   administration & dosage   pharmacokinetics   MeSH
• Cannabinoids * chemistry   administration & dosage   pharmacokinetics   MeSH
• Rats MeSH
• Nanoparticles chemistry   MeSH
• Rats, Sprague-Dawley MeSH
• Drug Compounding methods   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• cannabigerol MeSH Browser
• Emulsions MeSH
• Cannabidiol MeSH
• Cannabinoids * MeSH

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

• Keywords
• bioavailability, intestinal absorption, ivacaftor, lymphatic transport, pharmacokintetics,
• Publication type
• Journal Article MeSH