Browsing by Subject "In vitro digestion"

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    Relative bioavailability of curcumin as affected by formulation strategies : from in vitro digestion and cell culture experiments to human clinical trials
    (2022) Flory, Sandra; Frank, Jan
    Curcumin, the bioactive component of turmeric (Curcuma longa L.), has been used for thousands of years in traditional medicine for the prevention or treatment of several diseases and symptoms. Nowadays, curcumin is investigated worldwide as a nutritional supplement. To overcome the central limitation of its naturally low oral bioavailability, several formulation strategies have been developed, such as its co-administration with turmeric oils or piperine to inhibit its metabolism and efflux or its incorporation into micelles, cyclodextrin complexes or phospholipid bilayers to improve its stability and solubility. So far, the different formulations have not been compared directly, in one cohort of participants and at equal doses. The present doctoral thesis aimed, for the first time, at a direct comparison of the bioavailability of curcumin in form of a native curcuma extract or seven formulations, namely polysorbate 80 micelles, g-cyclodextrin complexes, liposomes, phytosomes, submicron-particle curcumin or curcumin administered with turmeric oils or piperine, in healthy adults. The project further aimed to investigate several critical factors for curcumin bioavailability in vitro and to explain thereby the observations made in vivo. In a randomized, double-blind crossover trial with 12 healthy participants (6 females, 6 males), curcumin pharmacokinetics, namely AUC (area under the plasma concentration-time curve), Cmax (maximum plasma concentration) and tmax (time to reach Cmax) were compared after administration of a single oral dose of 207 mg curcumin in form of a native curcuma extract or one of the seven formulations. Curcumin incorporated into polysorbate 80 micelles or g-cyclodextrin complexes showed 57-fold and 30-fold improved bioavailability compared to the native extract, whereas all other formulations showed no or minor effects. tmax of the better bioavailable formulations was smaller (1 to 2 hours) compared to all others (up to 7 hours). To compare the formulations regarding their digestion characteristics and transepithelial transport, in vitro digestion experiments followed by Caco-2 cell transport assays were conducted with the formulations normalized to their curcumin content. In parallel to the effects in vivo, curcumin showed higher stability, solubility and micellization efficiency when it was incorporated into polysorbate 80 micelles (100%, 80%, 55%) or g-cyclodextrin complexes (73%, 33%, 23%), whereas curcumin permeability through Caco-2 cell monolayers was not affected by its formulation. In the next study, curcumin efflux, partially mediated by P-glycoprotein (P-gp), was investigated, because the inhibition of curcumin efflux from the intestinal cells back to the intestinal lumen is targeted by the co-administration of curcumin with turmeric oils or piperine. In LS180 (colon adenocarcinoma) cells, native curcuma extract and the seven formulations were studied regarding cellular curcumin uptake within 1 hour and efflux within further 8 hours, as well as their effects on P-gp activity. Independently from its formulation, curcumin inhibited the activity of P-gp. Cellular curcumin uptake and efflux showed significant variability between formulations but no consistent effects. Cellular uptake and efflux may thus not be important for curcumin bioavailability in vivo. Another potential factor influencing bioavailability, that was investigated for native and micellar curcumin, was the time-dependent intracellular distribution in intestinal cells. Uptake and intracellular distribution in Caco-2 cells mainly did not differ between native and micellar curcumin. After 30 minutes, both were localized in lysosomes and mitochondria, after 180 minutes in peroxisomes and native curcumin also in mitochondria. The temporary localization in lysosomes is in line with the involvement of endocytosis in cellular uptake of curcumin. Nevertheless, the intracellular localization of curcumin was not affected by its incorporation into polysorbate 80 micelles. The data generated in this doctoral project thus demonstrate that the incorporation of curcumin into polysorbate 80 micelles or g-cyclodextrin complexes successfully improve its bioavailability. The improved bioavailability of both formulations can be explained by enhanced digestive stability, solubility and micellization efficiency and appears to be independent from post-digestive processes, such as intestinal permeability, cellular uptake, cellular efflux or intracellular distribution. Consequently, the present doctoral thesis delivers relevant information for the therapeutical application of curcumin, for the development of highly bioavailable formulations, as well as the basis for further clinical research on the health beneficial effects of curcumin.