Increasing Post‐Digestive Solubility of Curcumin Is the Most Successful Strategy to Improve its Oral Bioavailability: A Randomized Cross‐Over Trial in Healthy Adults and In Vitro Bioaccessibility Experiments

Abstract

Scope Different mechanistic approaches to improve the low oral bioavailability of curcumin have been developed, but not yet directly compared in humans. Methods and Results In a randomized, double‐blind, cross‐over trial with 12 healthy adults, the 24 h pharmacokinetics of a single dose of 207 mg curcumin is compared from the following formulations: native, liposomes, with turmeric oils, with adjuvants (including piperine), submicron‐particles, phytosomes, γ‐cyclodextrin complexes, and micelles. No free, but only conjugated curcumin is detected in all subjects. Compared to native curcumin, a significant increase in the area under the plasma concentration–time curve is observed for micellar curcumin (57‐fold) and the curcumin‐γ‐cyclodextrin complex (30‐fold) only. In vitro digestive stability, solubility, and micellization efficiency of micellar curcumin (100%, 80%, and 55%) and curcumin‐γ‐cyclodextrin complex (73%, 33%, and 23%) are higher compared to all other formulations (<72%, <8%, and <4%). The transport efficiencies through Caco‐2 cell monolayers of curcumin from the digested mixed‐micellar fractions did not differ significantly. Conclusion The improved oral bioavailability of micellar curcumin, and to a lesser extent of γ‐cyclodextrin curcumin complexes, appears to be facilitated by increased post‐digestive stability and solubility, whereas strategies targeting post‐absorptive processes, including inhibition of biotransformation, appear ineffective.

Uptake and time‐dependent subcellular localization of native and micellar curcumin in intestinal cells

“…To ensure quantifiable amounts of curcumin, the maximum non-toxic concentration of both formulations over the incubation time was chosen for all experiments. The maximum experimental time was 180 min to enable comparisons with published data on curcumin uptake in and permeability through Caco-2 cells monolayers 21,[27][28][29][30][31][32] and to avoid a loss of quantifiable intracellular curcumin concentrations with longer experimental times. 33 Toxicity was determined by neutral red uptake assay as previously described.…”

“…8,20 We then investigated potentially underlying mechanisms of improved curcumin bioavailability and identified increased digestive stability in combination with enhanced solubility and micellization efficiency as the most likely explanations. 21 Curcumin undergoes extensive metabolism in liver and intestine and the parent compound and its reductive metabolites are present in the circulation almost entirely as phase II metabolites, namely as glucuronide and sulfate conjugates but not in their unconjugated forms. 11,13,21 The phase II enzymes involved in the conjugation of curcumin to water-soluble metabolites are located in the membrane of the endoplasmic reticulum (ER).…”

Pharmaceutical Prospects of Curcuminoids for the Remedy of COVID-19: Truth or Myth

“…In all these clinical trials, curcumin/curcuminoids formulations are used as a therapeutic co-supplement in the treatment of COVID-19 patients ( Table 2 ). Because of the drawback of poor bioavailability of curcumin, several strategies are applied to improve the oral bioavailability of curcumin in clinical trials containing nano-delivery systems ( Hatamipour et al, 2019 ), with addition of adjuvants ( Tabanelli et al, 2021 ) and new formulation ( Flory et al, 2021 ). Inferiorly, the metabolic rate of curcumin is high in the intestine and liver, which causes its poor bioavailability.…”

An In Vitro and In Silico Study of Antioxidant Properties of Curcuminoid N-alkylpyridinium Salts: Initial Assessment of Their Antitumoral Properties

“…Different strategies have been used to improve it, including encapsulating or incorporating curcumin in a nanoparticle or microparticle drug delivery system, synthesizing more stable curcumin analogs that resist metabolism while retaining the pharmacological properties of curcumin, adding another natural product that has bio-enhancing properties to curcumin or a combination of two of these strategies [ 2 ]. Compared with native curcumin, micellar curcumin and curcumin-γ-cyclodextrin complexes exhibit greater bioavailability in humans, indicating that the post-digestive solubility is the most important factor to improve its pharmacokinetics [ 3 ].…”