Medicinal Plant Research 2025, Vol.15, No.6, 254-263 http://hortherbpublisher.com/index.php/mpr 259 within the liver and intestinal mucosa to glucuronide and sulfate conjugates, representing predominant forms detected in plasma. The majority of orally ingested curcumin is excreted unmetabolized in feces, and its elimination half-life is short, further limiting systemic bioavailability (Purpura et al., 2017). 6.2 Effects of food matrix, dosage, and formulation on bioavailability The bioavailability of curcumin heavily depends on the food matrix, dosage, and formulation. Co-administration with fats or oils increases absorption; however, at higher dosages, absorption becomes saturated, and rapid metabolism results in less than proportional increases in the plasma levels of the parent compound. Advanced formulation developments, such as nanoparticles, micelles, liposomes, phospholipid complexes, and cyclodextrin inclusion complexes, remarkably improve the solubility, stability, and absorption of curcumin, allowing higher and more sustained plasma concentrations compared to unformulated curcumin (Tabanelli et al., 2021; Hsu et al., 2025). 6.3 Strategies to improve bioavailability Various approaches have been developed to overcome poor bioavailability: adjuvants such as piperine that inhibit curcumin metabolism, formulation with essential oils such as BCM-95®, and encapsulation in nanoparticles, micelles, or liposomes. Such approaches increase absorption, prolong plasma residence time, and enhance therapeutic efficacy. Piperine, for example, can enhance curcumin bioavailability by up to 2000%, while new water-soluble or cyclodextrin-based formulations have achieved several-fold higher plasma levels (Tabanelli et al., 2021; Hsu et al., 2025). 6.4 Role of metabolites in physiological activities Therefore, curcumin undergoes extensive metabolism into conjugated forms, such as glucuronide and sulfate, and reduced forms like dihydrocurcumin and tetrahydrocurcumin. While these metabolites show, in some contexts, lesser activities compared to free curcumin, specific reduced metabolites retain or even increase antioxidant and anti-inflammatory activities. Their physiological relevance is currently under investigation since they could be responsible for the systemic effects of curcumin, even at the very low concentrations of its parental form (Cerullo et al., 2025; Hsu et al., 2025). 6.5 Gut microbiota-curcumin interactions and contribution to immune modulation Curcumin interacts bidirectionally with the gut microbiota. The microbiota metabolizes curcumin into active derivatives, whereas curcumin modulates the composition and function of the gut microbiome toward increasing the abundance of beneficial bacteria while suppressing pathogenic species. These interactions can improve intestinal barrier function, reduce inflammation, and thus contribute to immune modulation. Actually, the gut microbiota-curcumin axis is increasingly recognized as one of the key factors explaining curcumin’s health effects at low systemic bioavailability (Tabanelli et al., 2021; Cerullo et al., 2025). 7 Safety, Dosage, and Current Clinical Research onCurcuma longaand Curcumin 7.1 Safety and toxicological studies of curcumin andCurcuma longa Curcumin and Curcuma longa are generally recognized as safe for human consumption. Toxicological studies in animals show no mutagenic, genotoxic, or reproductive toxicity at standard doses, and acute oral LD50 values are high (>5,000 mg/kg in rats) (Zeng et al., 2022). Human studies have reported that oral curcumin is well tolerated up to 6-12 g/day for several weeks, with only mild gastrointestinal side effects in some cases (Zeng et al., 2022). According to EFSA, a derivative, tetrahydrocurcuminoids, is safe at 140 mg/d for adults (Turck et al., 2021). 7.2 Potential risks: Hepatotoxicity, drug interactions, etc. While curcumin is generally considered safe, some very rare instances of hepatotoxicity have been reported, generally following the compound in supplement form at very high dosages or when given in combination with piperine, which enhances the bioavailability of curcumin and may potentially inhibit drug-metabolizing enzymes such as CYP3A4 or P-glycoprotein. Most adverse effects are mild and relate to gastrointestinal upset; caution is warranted in individuals with liver disease or those taking medications dependent on hepatic metabolism (Stati et al., 2021; Zahra et al., 2024).
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