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.

Department of Analytical Chemistry Faculty of Science Charles University Hlavova 2030 8 128 43 Prague Czech Republic

Department of Chemical Engineering Faculty of Chemical Engineering University of Chemistry and Technology Technická 3 166 28 Prague Czech Republic

Institute of Pharmacology 1st Faculty of Medicine and General University Hospital Prague Charles University Albertov 4 128 00 Prague Czech Republic

Institute of Physics of the Czech Academy of Sciences Na Slovance 2 182 00 Prague Czech Republic

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