Pharmacokinetics-Driven Evaluation of the Antioxidant Activity of Curcuminoids and Their Major Reduced Metabolites-A Medicinal Chemistry Approach.

Curcuminoids are the main bioactive components of the well-known Asian spice and traditional medicine turmeric. Curcuminoids have poor chemical stability and bioavailability; in vivo they are rapidly metabolized to a set of bioreduced derivatives and/or glucuronide and sulfate conjugates. The reduced curcuminoid metabolites were also reported to exert various bioactivities in vitro and in vivo. In this work, we aimed to perform a comparative evaluation of curcuminoids and their hydrogenated metabolites from a medicinal chemistry point of view, by determining a set of key pharmacokinetic parameters and evaluating antioxidant potential in relation to such properties.Reduced metabolites were prepared from curcumin and demethoxycurcumin through continuous-flow hydrogenation. As selected pharmacokinetic parameters, kinetic solubility, chemical stability, metabolic stability in human liver microsomes, and parallel artificial membrane permeability assay (PAMPA)-based gastrointestinal and blood-brain barrier permeability were determined. Experimentally determined logP for hydrocurcumins in octanol-water and toluene-water systems provided valuable data on the tendency for intramolecular hydrogen bonding by these compounds. Drug likeness of the compounds were further evaluated by a in silico calculations. Antioxidant properties in diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and oxygen radical absorbance capacity (ORAC) assays were comparatively evaluated through the determination of ligand lipophilic efficiency (LLE). Our results showed dramatically increased water solubility and chemical stability for the reduced metabolites as compared to their corresponding parent compound. Hexahydrocurcumin was found the best candidate for drug development based on a complex pharmacokinetical comparison and high LLE values for its antioxidant properties. Development of tetrahydrocurcumin and tetrahydro-demethoxycurcumin would be limited by their very poor metabolic stability, therefore such an effort would rely on formulations bypassing first-pass metabolism.

Comparative bioavailability of curcuminoids from a water-dispersible high curcuminoid turmeric extract against a generic turmeric extract: a randomized, cross-over, comparative, pharmacokinetic study.

OBJECTIVES: The therapeutic utility of turmeric (Curcuma longa L., Zingiberaceae) is limited due to low bioavailability of its active principal curcuminoids. This study evaluates the pharmacokinetic characteristics of a natural, water-dispersible turmeric extract containing 60% curcuminoids (TurmXtra 60N), referred to as WDTE60N, compared to standard turmeric extract 95% (STE95). METHODS: This open-label, two-way crossover, single oral dose, comparative pharmacokinetic study, randomized 14 subjects to receive one capsule of WDTE60N (150 mg curcuminoids) or three capsules of STE95 (500 mg curcuminoids each). The resulting dose ratio of actives for WDTE60N:STE95 was 1:10. KEY FINDINGS: Peak plasma levels of free curcumin, total curcuminoids, tetrahydrocurcumin and demethoxycurcumin were similar (P > 0.05). Cmax of total curcumin was higher (P = 0.0253) for WDTE60N at a 10-fold lower dose compared to STE95 (43.5 ± 28.5 vs. 21.3 ± 10.7 ng/ml). Mean AUC0-t was higher (P < 0.001) for free curcumin and comparable for total curcumin and total curcuminoids with WDTE60N than with STE95. Five adverse events were reported in three subjects (mild in severity) and were unrelated to study products. CONCLUSION: WDTE60N showed higher absorption and comparable exposure for free curcumin, total curcumin and total curcuminoids at a 10-fold lower dose than STE95.

A novel predict-verify strategy for targeted metabolomics: Comparison of the curcuminoids between crude and fermented turmeric.

Curcuminoids are the major bioactive constituents of turmeric, the application of which are limited by the poor bioavailability. In this study, turmeric was fermented by the Monascus purpureus and Eurotium cristatum fungi to enhance its bioavailability. To explore the variations in the curcuminoids contents in fermented turmeric, a targeted predict-verify strategy was established. For targeted analysis of curcuminoids, a compound library containing all possible curcuminoids based on their structural skeleton was predicted and built for targeted scanning. Then, the MS data were automatically matched with the predicted library to verify the corresponding curcuminoids. As a result, 115 curcuminoids (48 novel compounds and 14 compounds reported in turmeric for the first time) were fully characterized in crude and fermented turmeric. Among these curcuminoids, 31 were newly generated in fermented turmeric. The established predict-verify strategy allows for an efficient and automatic metabolomic analysis to screen for curcuminoids with potentially better bioavailability.

Effect of different oleogelators on lipolysis and curcuminoid bioaccessibility upon in vitro digestion of sunflower oil oleogels.

Sunflower oil enriched with curcuminoid compounds (CUs) was gelled by adding 5% (w/w) saturated monoglycerides (MG), rice bran waxes (RW) or a mixture of ß-sitosterol and γ-oryzanol (PS). The resulting oleogels differed for rheological properties and firmness due to the difference in gel network structure. PS oleogel was the firmest sample followed by RW and MG ones. Upon in vitro digestion, fatty acid release as a function of digestion time was greatly affected by oleogel structure: the extent of lipolysis decreased as oleogel strength increased (PS < RW < MG). On the other hand, the nature of the oleogelator affected CUs bioaccessibility, which was lower in oleogels containing crystalline particles (MG and RW). These findings appear interesting in the attempt to develop oleogels able to control lipid digestion as well as to deliver bioactive molecules in food systems.

Curcuminoids plus piperine improve nonalcoholic fatty liver disease: A clinical trial.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) as a prevalent hepatic disease is associated with an increased risk of morbidity and mortality related to the liver and cardiovascular disease (CVD). Lifestyle modification and good metabolic control is the first line of treatment, but not always efficacious in reversing NAFLD pathogenesis. Curcumin is a dietary phytochemical with hepatoprotective activities, though its low bioavailability is considered as a major challenge for clinical applications. Therefore, in this study, in order to improve the bioavailability of curcumin, it was coadministered with piperine and we investigated the effects of this bioavailability-enhanced curcumin on serum hepatic enzymes, lipid profile, and glycemic indices in patients with NAFLD. METHODS: In this randomized controlled parallel-group trial, 70 subjects with ultrasound-determined NAFLD were randomized to either 500 mg curcuminoids coadministered with 5 mg piperine daily or placebo for 12 weeks. NAFLD severity (on the basis of sonography) and hepatic function was assessed at baseline and at the study end. RESULTS: Seventy subjects completed the study. Supplementation with curcuminoids plus piperine significantly reduced the hematocrit (P = 0.027), erythrocyte sedimentation rate (P = 0.048) and the serum concentrations of alanine aminotransferase (P = 0.035), aspartate aminotransferase (P = 0.042), alkaline phosphatase (P = 0.004), cholesterol (P < 0.016), low-density lipoprotein cholesterol (P < 0.017), Iron (P = 0.026), and Hemoglobin (P = 0.025) and increased total iron-binding capacity (P = 0.003). However, except albumin, changes in other parameters were not statistically different between groups. In addition, administration of curcuminoids plus piperine significantly improved NAFLD severity (P < 0.001), which was statistically different compared with the placebo group (P = 0.022). Also, the percentage of improved patients was marginally higher in the curcuminoids plus piperine group when compared with the placebo group (P = 0.058). CONCLUSION: This study suggested beneficial effects of combined curcuminoids and piperine supplementation on disease severity in patients with NAFLD.

Increased in situ intestinal absorption of phytoestrogenic diarylheptanoids from Curcuma comosa in nanoemulsions.

Curcuma comosa has long been used as a gynecological medicine. Several diarylheptanoids have been purified from this plant, and their pharmacological effects were proven. However, there is no information about the absorption of C. comosa components to support the formulation usage. In the present study, C. comosa hexane extract and the mixture of its two major compounds, (4E,6E)-1,7-diphenylhepta-4,6-dien-3-ol (DA1) and (6E)-1,7-diphenylhept-6-en-3-ol (DA2), were formulated into nanoemulsions. The physical properties of the nanoemulsions and the in situ intestinal absorptions of DA1 and DA2 were evaluated. The results demonstrated the mean particle sizes at 0.207 ± 0.001 and 0.408 ± 0.014 µm, and the zeta potential at -14.57 ± 0.85 and -10.47 ± 0.32 mV for C. comosa nanoemulsion (C.c-Nano) and mixture of diarlylheptanoid nanoemulsions (DA-Nano), respectively. The entrapments of DA1 and DA2 were 76.61% and 75.41%, and 71.91% and 71.63% for C.c-Nano and DA-Nano, respectively. The drug loading ratios of DA1 and DA2 were 351.47 and 614.53 µg/mg, and 59.48 and 126.72 µg/mg for C.c-Nano and DA-Nano. The intestinal absorption rates of DA1 and DA2 were 0.329 ± 0.015 and 0.519 ± 0.026 µg/min/cm2 in C.c-Nano, and 0.380 ± 0.006 and 0.428 ± 0.036 µg/min/cm2 in DA-Nano, which were five to ten times faster than those in oil. In conclusion, the formulation in nanoemulsion forms obviously increased the intestinal absorption rate of diarylheptanoids.

Pharmacokinetics and organ distribution of diarylheptanoid phytoestrogens from Curcuma comosa in rats.

Curcuma comosa is widely used as a traditional herbal medicine for gynecological diseases in South East Asia. Previous studies reported that it has phytoestrogenic activity, and several diarylheptanoids were found to be the active constituents. In this study, the pharmacokinetics profile and organ distribution of three active compounds of C. comosa hexane extract were investigated. Rats were separately administered C. comosa hexane extract intravenously at the dose of 125 mg/kg and orally at the doses of 125 and 250 mg/kg body weight, after which blood and target organs were collected at specified time intervals from 0 to 24 h. HPLC was used to measure the concentration of three major compounds, (6E)-1,7-diphenylhept-6-en-3-one (DPH1), (4E,6E)-1,7-diphenylhepta-4,6-dien-3-ol (DPH2), and (6E)-1,7-diphenylhept-6-en-3-ol (DPH3), which were found to be present in the blood and tissues and were subsequently used as markers. In the intravenous study, the volumes of distribution (V(d)) were 1.06, 8.57, and 6.56 L/kg and clearance values (CL(s)) were 0.28, 5.56, and 3.39 L/kg/h for DPH1, DPH2, and DPH3, respectively. After oral administration, the three major compounds of both doses reached a maximum systemic concentration at 2 h with maximum concentration (C(max)) of 0.85, 0.17, and 0.53 mg/L for the lower dose and 1.46, 0.17, and 0.61 mg/L for the higher dose. The bioavailabilities were 31.2, 24.01, and 31.56% for lower dose and 22.61, 17.66, and 17.73% for higher dose with a terminal half-life (t(1/2)) of 10.86, 6.3, and 4.62 h for lower dose and 3.85, 2.77, and 2.10 h for higher dose for DPH1, DPH2, and DPH3, respectively. These three major compounds are all found distributed in the brain, liver, kidneys, ovaries, and uterus after oral and intravenous administration and their related pharmacokinetic parameters are described. This study provides the essential pharmacokinetic data for diarylheptanoid phytoestrogenic compounds of C. comosa extract which are required for clinical dose and dosage design.