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Kaempferia parviflora Wall. ex Baker (KP), Krachaidam in Thai or Thai ginseng, is a herbal medicine that has many potential pharmacological effects. The effect of KP extract on blood glucose level in rodent was reported. This study focused on the oral glucose tolerance test and pharmacokinetic study in healthy volunteers administered with KP extract (90 and 180 mg/day, placebo). The oral glucose tolerance tests were performed at baselines and 28-days of administration. The pharmacokinetics were determined after a single dose administration of the tested products using 3,5,7,3′,4′-pentamethoxyflavone (PMF) and 5,7,4′-trimethoxylflavone (TMF) as markers. The results showed that glucose metabolism via oral glucose tolerance test was not affected by KP extract. Blood glucose levels of volunteers at 120 min after glucose loading were able to be returned to initial levels in placebo, KP 90 mg/day, and KP 180 mg/day groups both at baseline and 28-days of administration. The results of the pharmacokinetic study revealed that only TMF and PMF, but not 5,7-dimethoxyflavone (DMF) levels could be detected in human blood. The given doses of KP extract at 90 and 180 mg/day showed a linear dose-relationship of blood PMF concentration whereas blood TMF was detected only at high given dose (180 mg/day). The half-lives of PMF and TMF were 2–3 h. The maximum concentration (Cmax), area under the curve of blood concentration and time (AUC), and time to maximum concentration (Tmax) values of PMF and TMF estimated for the 180 mg/day dose were 71.2 ± 11.3, 63.0 ± 18.0 ng/mL; 291.9 ± 48.2, 412.2 ± 203.7 ng∙h/mL; and 4.02 ± 0.37, 6.03 ± 0.96 h, respectively. PMF was quickly eliminated with higher Ke and Cl than TMF at the dose of 180 mg/day of KP extract. In conclusion, the results demonstrated that KP extract had no effect on the glucose tolerance test. In addition, this is the first demonstration of the pharmacokinetic parameters of methoxyflavones of KP extract in healthy volunteers. The data suggest the safety of the KP extract and will be of benefit for further clinical trials using KP extract as food and sport supplements as well as a drug in health product development.

Nobiletin (NOB), a flavonoid, has extremely low water solubility and low oral bioavailability; however, despite these problems, various physiological effects have been investigated in vitro . In the present study, we investigated the transdermal delivery of NOB using choline and geranic acid (CAGE), which is a biocompatible material that has been reported to be a promising transdermal delivery approach. The feasibility was evaluated by a set of in vitro and in vivo tests. A solubility evaluation demonstrated that CAGE induced excellent solubility of NOB induced by multipoint hydrogen bonding between NOB and CAGE. In vitro transdermal tests using a Franz diffusion cell showed that CAGE was effective in enhancing transdermal absorption of NOB, compared to other penetration enhancers. Subsequent in vivo tests demonstrated that CAGE significantly improved area under the concentration-time curve of NOB in vivo and NOB/CAGE sample showed 20-times higher bioavailability than oral administration of NOB crystal. Furthermore, NOB/CAGE sample also showed significant drops of the blood glucose level in rats derived from hypoglycemic activity of NOB. Thus, transdermal administration of NOB using CAGE was shown to be feasible, which indicates that the use of CAGE may be adapted for other flavonoids that also show both low water solubility and low permeability.

Pueraria lobata (Willd.) Ohwi is a medicinal and edible homologous plant with a long history in China. Puerarin, the main component isolated from the root of Pueraria lobata, possesses a wide range of pharmacological properties. Daidzein and glucuronides are the main metabolites of puerarin and are excreted in the urine and feces. As active substrates of P-gp, multidrug resistance-associated protein and multiple metabolic enzymes, the pharmacokinetics of puerarin can be influenced by different pathological conditions and drug-drug interactions. Due to the poor water-solubility and liposolubility, the applications of puerarin are limited. So far, only puerarin injections and eye drops are on the market. Recent years, researches on improving the bioavailability of puerarin are developing rapidly, various nanotechnologies and preparation technologies including microemulsions and SMEDDS, dendrimers, nanoparticles and nanocrystals have been researched to improve the bioavailability of puerarin. In order to achieve biocompatibility and desired activity, more effective quality evaluations of nanocarriers are required. In this review, we summarize the pharmacokinetics and drug delivery systems of puerarin up to date.

Flavonoids are phytochemicals that are well known for their beneficial pharmacological properties. Diosmin is a flavone glycoside derived from hesperidin, a flavanone abundantly found in citrus fruits. Daflon is an oral phlebotonic flavonoid combination containing diosmin and hesperidin (9:1) that is commonly used for the management of blood vessel disorders. After oral administration, diosmin is converted to diosmetin, which is subsequently absorbed and esterified into glucuronide conjugates that are excreted in the urine. Pharmacological effects of diosmin have been investigated in several in vitro and in vivo studies, and it was found to possess anti-inflammatory, antioxidant, antidiabetic, antihyperlipidemic, and antifibrotic effects in different disease models. Diosmin also demonstrated multiple desirable properties in several clinical studies. Moreover, toxicological studies showed that diosmin has a favorable safety profile. Accordingly, diosmin is a potential effective and safe treatment for many diseases. However, diosmin exhibits inhibitory effects on different metabolic enzymes. This encourages the investigation of its potential therapeutic effect and safety in different diseases in clinical trials, while taking potential interactions into consideration.Graphic Abstract

Tangeretin, 4′,5,6,7,8-pentamethoxyflavone, is one of the major polymethoxyflavones (PMFs) existing in citrus fruits, particularly in the peels of sweet oranges and mandarins. Tangeretin has been reported to possess several beneficial bioactivities including anti-inflammatory, anti-proliferative and neuroprotective effects. To achieve a thorough understanding of the biological actions of tangeretin in vivo, our current study is designed to investigate the pharmacokinetics, bioavailability, distribution and excretion of tangeretin in rats. After oral administration of 50 mg/kg bw tangeretin to rats, the Cmax, Tmax and t1/2 were 0.87 ± 0.33 μg/mL, 340.00 ± 48.99 min and 342.43 ± 71.27 min, respectively. Based on the area under the curves (AUC) of oral and intravenous administration of tangeretin, calculated absolute oral bioavailability was 27.11%. During tissue distribution, maximum concentrations of tangeretin in the vital organs occurred at 4 or 8 h after oral administration. The highest accumulation of tangeretin was found in the kidney, lung and liver, followed by spleen and heart. In the gastrointestinal tract, maximum concentrations of tangeretin in the stomach and small intestine were found at 4 h, while in the cecum, colon and rectum, tangeretin reached the maximum concentrations at 12 h. Tangeretin excreted in the urine and feces was recovered within 48 h after oral administration, concentrations were only 0.0026% and 7.54%, respectively. These results suggest that tangeretin was mainly eliminated as metabolites. In conclusion, our study provides useful information regarding absorption, distribution, as well as excretion of tangeretin, which will provide a good base for studying the mechanism of its biological effects. [Display omitted] •Absolute oral bioavailability of tangeretin in rats was 27.11%.•Tangeretin was mainly concentrated in the kidney, lung and liver.•Less than 8% of tangeretin excreted in either urine or feces.

A kind of hydroxylated polymethoxyflavone (PMFs) existing in the citrus genus, 5-Demethyltangeretin (5-DTAN), has been reported to possess several bioactivities in vitro and in vivo. The aim of this study was to investigate whether acetylation could enhance the anticancer activity and oral bioavailability of 5-DTAN. PC-3 human prostate cancer cells were treated with tangeretin (TAN), 5-DTAN, and 5-acetylated TAN (5-ATAN), and the results showed that the cytotoxic effect 5-ATAN (IC50 value of 5.1 µM) on the cell viability of PC-3 cells was stronger than that of TAN (IC50 value of 17.2 µM) and 5-DTAN (IC50 value of 11.8 µM). Compared to 5-DTAN, 5-ATAN treatment caused a more pronounced DNA ladder, increased the sub-G1 phase population, and induced G2/M phase arrest in the cell cycle of PC-3 cells. We also found that 5-ATAN triggered the activation of caspase-3 and the progression of the intrinsic mitochondrial pathway in PC-3 cells, suggesting the induction of apoptosis. In a cell wound healing test, 5-ATAN dose-dependently reduced the cell migration, and the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) was decreased after 48 h of 5-ATAN treatment. Moreover, oral administration of 5-ATAN showed a significantly stronger inhibitory effect on tumor size and tumor weight in tumor-bearing nude mice than those of vehicle or the 5-DTAN group (p < 0.05). Furthermore, pharmacokinetic results showed that single-dose oral administration of 5-ATAN exhibited a higher maximum concentration (Cmax) and area under the curve (AUC) of 5-DTAN in plasma than that of 5-DTAN. More extensive distribution of 5-DTAN to most tissues of mice was also observed in mice treated with 5-ATAN for 7 days. In conclusion, acetylation strongly enhances the anticancer activity and oral bioavailability of 5-DTAN and could be a promising strategy to promote the potential bioactivities of natural products.

(1) Background: The aerial part of G. uralensis had pharmacological effects against chronic non-bacterial prostatitis (CNP), and flavonoids are the main efficacy components. The purpose of this study was to obtain the pharmacokinetics, prostate distribution and metabolic characteristics of some flavonoids in rats. (2) Methods: The prototype flavones and the metabolites of four representative flavonoids, namely puerarin, luteolin, kaempferol and pinocembrin in plasma, prostate, urine and feces of rats were analyzed by UPLC-Q-Exactive Orbitrap-MS. In addition, the pharmacokinetic parameters in plasma and distribution of prostate of four components were analyzed by HPLC-MS/MS. (3) Results: In total, 22, 17, 22 and 11 prototype flavones were detected in the prostate, plasma, urine and feces, respectively. The metabolites of puerarin in the prostate are hydrolysis and glucose-conjugated products, the metabolites of kaempferol and luteolin in the prostate are methylation and glucuronidation, and the metabolites of pinocembrin in the prostate are naringenin, oxidation, sulfation, methylation and glucuronidation products. The t1/2 of puerarin, luteolin, kaempferol and pinocembrin was 6.43 ± 0.20, 31.08 ± 1.17, 18.98 ± 1.46 and 13.18 ± 0.72 h, respectively. The concentrations of the four flavonoids in prostate were ranked as kaempferol > pinocembrin > luteolin > puerarin. (4) Conclusions: Methylation and glucuronidation metabolites were the main metabolites detected in the prostate. A sensitive and validated HPLC–MS/MS method for simultaneous determination of puerarin, luteolin, kaempferol and pinocembrin in rat plasma and prostate was described, and it was successfully applied to the pharmacokinetic and prostate distribution studies.

The aim of this work was to increase the solubility and oral bioavailability of isorhamnetin, kaempferol, and quercetin in the total flavones of Hippophae rhamnoides L. (TFH) by preparing their nanosuspensions (NSs) and an inclusion complex. Based on the particle size and zeta potential, P407, Soluplus, SDS, PEG-6000, and HP-β-CD were selected as stabilizers. TFH NSs and a TFH/HP-β-CD inclusion complex were prepared, and their morphology, crystallinity, molecular interactions, and cytotoxicity were investigated. Furthermore, the saturation solubility, dissolution, and pharmacokinetics of the three flavonoids in the TFH, TFH NSs, and TFH/HP-β-CD inclusion complex were compared. The five obtained TFH NSs were physically stable, and their particle sizes were all below 200 nm. The solubility and dissolution of the three active components were obviously enhanced by the formation of the TFH NSs and TFH/HP-β-CD inclusion complex. Correspondingly, the oral bioavailability of isorhamnetin, kaempferol, and quercetin increased up to 4.11-, 3.85-, and 6.73-fold, respectively, in the TFH NSs and 2.89-, 3.71-, and 9.51-fold, respectively, in the TFH/HP-β-CD inclusion complexes compared to those in the raw TFH. In brief, both NSs and inclusion complexes can improve the oral bioavailability of the three flavonoids in TFH. Taking the drug loading and the stable ratio of the multiple components into consideration, the NSs is a more promising strategy than the inclusion complex for increasing the oral bioavailability of multiple water-insoluble components in herbal extracts.[Images not available. See PDF.]Graphical abstract

To enhance the bioavailability of hydrophobic nobiletin (NOB), this study constructed nanoparticles (LT-NOB) via self-assembly of lysozyme and tannic acid (TA). The multivalent weak interaction network between TA and lysozyme effectively encapsulated amorphous NOB, inhibiting crystallization. The optimized LT-NOB exhibited a size of 212 nm, high encapsulation efficiency (89.5%), and drug loading (47.25%). Cellular uptake was significantly improved, primarily through macropinocytosis, followed by lysosomal escape and endoplasmic reticulum targeting. In Caco-2 and co-culture models, LT-NOB enhanced mucosal permeation by 75% and 50%, respectively, compared to free NOB. This work elucidates a robust strategy for stabilizing amorphous drugs and promoting their intestinal absorption, providing a foundation for advanced nanodrug delivery.

Hispidulin is a naturally occurring flavone known to have various Central nervous system (CNS) activities. Proposed synthetic approaches to synthesizing hispidulin have proven unsatisfactory due to their low feasibility and poor overall yields. To solve these problems, this study developed a novel scheme for synthesizing hispidulin, which had an improved overall yield as well as more concise reaction steps compared to previous methods reported. Additionally, using the same synthetic strategy, d-labelled hispidulin was synthesized to investigate its metabolic stability against human liver microsome. This work may produce new chemical entities for enriching the library of hispidulin-derived compounds.