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.

• Klíčová slova
• cannabinoids, lymph-targeting, lymphatic transport, nanoemulsion, oral bioavailability, pharmacokinetics, quantitative structure−activity relationship (QSAR),
• MeSH
• aplikace orální MeSH
• biologická dostupnost MeSH
• biologický transport MeSH
• emulze chemie   MeSH
• kanabidiol chemie   aplikace a dávkování   farmakokinetika   MeSH
• kanabinoidy * chemie   aplikace a dávkování   farmakokinetika   MeSH
• krysa rodu Rattus MeSH
• nanočástice chemie   MeSH
• potkani Sprague-Dawley MeSH
• příprava léků metody   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cannabigerol MeSH Prohlížeč
• emulze MeSH
• kanabidiol MeSH
• kanabinoidy * 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.

• Klíčová slova
• bioavailability, intestinal absorption, ivacaftor, lymphatic transport, pharmacokintetics,
• Publikační typ
• časopisecké články MeSH

Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease with unknown cause. It mainly affects joints and, without proper treatment, negatively impacts their movement, causes painful deformities, and reduces the patients' quality of life. Current treatment options consist of various types of disease-modifying antirheumatic drugs (DMARDs), however 20-30% of patients are partially resistant to them. Therefore, development of new drugs is necessary. Possible option are compounds exhibiting their action via endocannabinoid system, which plays an important role in pain and inflammation modulation. One such compound - cannabidiol (CBD) has already been shown to attenuate synovitis in animal model of RA in in vivo studies. However, it has low bioavailability due to its low water solubility and lipophilicity. This issue can be addressed by preparation of a lipid containing formulation targeting lymphatic system, another route of absorption in the body. Materials and Methods: CBD-containing emulsion was prepared by high-shear homogenization and its droplet size distribution was analysed by optical microscopy. The relative oral bioavailability compared to oil solution as well as total availability of CBD were assessed in a cross-over study in rats and absorption of CBD via lymphatic system was observed. The effect of CBD on the animal model of RA was determined. Results: Compared to oil solution, the emulsion exhibited higher absolute oral bioavailability. Significant lymphatic transport of CBD was observed in all formulations and the concentrations in lymph were calculated. The therapeutic effect of CBD on RA was confirmed as an improvement in clinical symptoms as well as morphological signs of disease activity were observed during the study. Conclusion: In this work, we prepared a simple stable emulsion formulation, determined the pharmacokinetic parameters of CBD and calculated its absolute bioavailability in rats. Moreover, we successfully tested the pharmaceutical application of such a formulation and demonstrated the positive effect of CBD in an animal model of RA.

• Klíčová slova
• bioavailability, cannabidiol, emulsion, in vivo study, lymphatic absorption, rheumatoid arthritis,
• MeSH
• aplikace orální MeSH
• bolest farmakoterapie   MeSH
• emulze MeSH
• kanabidiol * farmakologie   chemie   MeSH
• klinické křížové studie MeSH
• krysa rodu Rattus MeSH
• kvalita života MeSH
• revmatoidní artritida * farmakoterapie   MeSH
• voda MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• emulze MeSH
• kanabidiol * MeSH
• voda MeSH