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Progress to Improve Oral Bioavailability and Beneficial Effects of Resveratrol

resveratrol derivatives resveratrol bioavailability resveratrol resveratrol delivery systems

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#1 Engadin

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Posted 01 June 2019 - 10:21 AM



Resveratrol (3,5,4′-trihydroxystilbene; RSV) is a natural nonflavonoid polyphenol present in many species of plants, particularly in grapes, blueberries, and peanuts. Several in vitro and in vivo studies have shown that in addition to antioxidant, anti-inflammatory, cardioprotective and neuroprotective actions, it exhibits antitumor properties. In mammalian models, RSV is extensively metabolized and rapidly eliminated and therefore it shows a poor bioavailability, in spite it of its lipophilic nature. During the past decade, in order to improve RSV low aqueous solubility, absorption, membrane transport, and its poor bioavailability, various methodological approaches and different synthetic derivatives have been developed. In this review, we will describe the strategies used to improve pharmacokinetic characteristics and then beneficial effects of RSV. These methodological approaches include RSV nanoencapsulation in lipid nanocarriers or liposomes, nanoemulsions, micelles, insertion into polymeric particles, solid dispersions, and nanocrystals. Moreover, the biological results obtained on several synthetic derivatives containing different substituents, such as methoxylic, hydroxylic groups, or halogens on the RSV aromatic rings, will be described. Results reported in the literature are encouraging but require additional in vivo studies, to support clinical applications.



1. Health Beneficial Effects of Resveratrol (RSV)


Natural products have recently aroused interest within the scientific community for their beneficial effects on several diseases. Preclinical, clinical, and epidemiological studies have shown that consumption of polyphenols contained in cereals, legumes, vegetables, and fruit at high levels, prevents various diseases, including cancer. The most promising candidate is resveratrol (RSV), a natural nonflavonoid polyphenol found in numerous plant species, in particular in grapes, blueberries, and peanuts [1]. RSV or 3,5,4′-trihydroxystilbene consists of two aromatic rings that are connected through a methylenic bridge (Figure 1). It exists as two geometrical isomers—the trans-RSV form (Figure 1B) and the cis-form—the first having the greater stability and biological activity and the second being less active (Figure 1A). The last form arises from isomerization of the trans-form following the breakdown of the RSV molecule due to the action of UV light during the fermentation of grape skins or under high pH conditions [2].


It is known that polyphenols exert antioxidant effects related to the presence of hydroxylic groups which participate in mechanisms aimed to decrease reactive oxygen species (ROS) and free radicals and to increase endogenous antioxidants biosynthesis [6]. RSV antioxidant properties have been attributed to its capability to reduce copper-catalyzed oxidation [7] and inhibit lipid peroxidation of low density lipoproteins (LDL) [8] and cellular membranes [9]. Other studies demonstrated that RSV decreases intracellular concentration of apolipoprotein B (ApoB), cholesterol esters, and triglyceride secretion rate, thus protecting against atherosclerosis [10]. RSV anti-inflammatory effects are mainly due to the inhibition of cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), and 5-lipoxygenase catalytic activity, and consequent suppression of prostaglandins, thromboxanes, and leukotriene formation [11]. It has been observed how this compound attenuated macrophage/mast cell-derived proinflammatory factors such as platelet-activating factor (PAF), tumor necrosis factor-α (TNF-α), and histamine [12]. In addition, RSV is able to inhibit chemotactic factors formation and platelet aggregation [13] supporting cardioprotective effects [14]. It has been reported that it determines an increase in the expression of endothelium nitric synthase (eNOS) and in the synthesis of nitric oxide (NO) restoring the endothelial dysfunction [15]. Furthermore, RSV has neuroprotective activity, as evidenced by its capability to improve cellular stress resistance and longevity, by increasing the activity of SIRT1 [16]: a member of the sirtuins family, comprising proteins that possess either mono-ADP-ribosyltransferase or deacetylase activity [17]. Moreover, it has been observed that RSV-induced SIRT1 activity, through disruption of the Toll-like receptor 4/nuclear factor κ-light-chain enhancer of activated B cells/signal transducer and activator of transcription (TLR4/NF-κB/STAT) signaling, reduces cytokines production in activated microglia [18]. In particular, RSV displays important neuroprotective effects on animal models with Parkinson’s disease and prevents free radical-mediated damage of neuronal cells through the activation of SIRT1 pathway [19].


On the other hand, it has been demonstrated that RSV possesses cancer chemopreventive and chemotherapeutic activity [4]. RSV chemopreventive effects are attributed mainly to the inhibition of cyclooxygenases [20,21], NF-κB [22], kinases such as protein kinase C [23] or reduced cytochrome P450, family 1, and member A1 and B1 (CYP1A1 and CYP1B1) gene expression [24]. CYP1A1 and CYP1B1 genes encode for enzymes that play a central role in metabolic activation of several procarcinogens and in the detoxification from different xenobiotic compounds [25]. Antitumor properties of RSV were demonstrated in vitro in several tumors [26] including lymphoblastic leukemia [27], colon [28], pancreatic [29], melanoma [30], gastric [31], cervical [32], ovarian [33], endometrial [34], liver [35], prostate [36], and breast [37]. These properties are mainly due to its proapoptotic and antiproliferative actions. Furthermore, RSV increases the efficacy of traditional chemotherapy and radiotherapy decreasing resistance and sensitizing tumor cells to chemotherapeutic agents [38]. Moreover, preclinical in vivo studies [39] and clinical trials confirmed its relevant antitumor actions [38,40,41,42].




2. Pharmacokinetic Characteristics of RSV


Although several reports confirmed that RSV possesses health beneficial effects, this compound shows peculiar pharmacokinetic characteristics that limit its use. In mammals, RSV is extensively metabolized and rapidly eliminated and therefore it shows a poor bioavailability [43,44]. After oral administration, RSV is absorbed at the intestinal level by passive diffusion or by membrane transporters and then released in the bloodstream where it can be detected as unmodified or metabolized molecule [45]. In fact, in the intestine, this compound undergoes a presystemic metabolism through first-pass glucuronidation and sulfate conjugation of the phenolic groups and hydrogenation of the aliphatic double bond [45]. In the bloodstream, RSV can bind to albumin and lipoproteins, such as LDL, thus forming complexes which, in turn, can be dissociated at the cellular membrane where albumin and LDL interact with the relative receptors allowing RSV entrance into cells [46]. Phase II metabolism of RSV and its metabolites occurs in the liver. Five different metabolites were detected in the urine: RSV monosulfate, two isomeric forms of RSV monoglucuronide, monosulfate dihydro-RSV, and monoglucuronide dihydro-RSV [45,47]. It has been reported that the majority of plasma RSV metabolites are RSV-3-O-sulfate, RSV-4′-O-glucuronide, and RSV-3-O-glucuronide, all with very little bioactivity, even if RSV-3-O-sulfate possesses estrogen receptor α-preferential antagonistic activity [48]. Moreover, extremely rapid sulfate conjugation by the intestine/liver appears to be the rate-limiting step in RSV bioavailability [44]. It has been demonstrated that both sulfates and glucuronides can be converted to RSV in target tissues such as liver [49]. In addition, RSV metabolites undergo enterohepatic recirculation, which allows its deconjugation in the small intestine and reabsorption [50].


Although RSV is quickly metabolized, oral administration is the preferred and only viable route, except for topical application. It is known that plasma concentration of the unchanged RSV depends on the dosages ingested. Several preclinical studies aimed to determine the appropriate RSV oral dosage and bioavailability in humans [51,52]. It has been demonstrated that oral dose of 25 mg of RSV resulted in plasma concentration for unchanged RSV in the range of 1 to 5 ng/mL [44]. Administration of higher doses (up to 5 g) led to the increase of unchanged RSV up to 530 ng/mL, indicating how after a high RSV dose only a low amount of the unchanged RSV is present in the plasma [53]. Even if RSV seems to be well tolerated and safe, administration of higher oral doses does not allow to improve therapeutic effects [53], but, instead, may be the cause of the side effects observed at the dose of 1 g/kg (body weight) including diarrhea, nausea, and abdominal pain [51]. Therefore, based on the findings from clinical studies, it appears that the main obstacle that must be overcome to consider RSV as a therapeutic agent is its low bioavailability [54]. For this reason, the researches focused on improving pharmacokinetic profile of RSV.





F U L L   T E X T :   International Journal of Molecular Science


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#2 Woody42

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Posted 16 June 2019 - 01:09 PM

This article discuses the solubility of RSV in different  solvents . You

will note it's insoluble in water but somewhat soluble in oils and very

solvable in either  ethanol  or PEG 400 .     


Pre-formulation studies of resveratrol

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#3 peoplepleaser101

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Posted 17 November 2019 - 02:36 PM

There is no need for that, piperine increases Resveratrol bioavailability by ca 1500%, here look:


 Mice were administered resveratrol (100 mg/kg; oral gavage) or resveratrol (100 mg/kg; oral gavage)+piperine (10 mg/kg; oral gavage), and the serum levels of resveratrol and resveratrol-3-O-β-D-glucuronide were analyzed at different times. We found that the degree of exposure (i.e. AUC) to resveratrol was enhanced to 229% and the maximum serum concentration (C(max)) was increased to 1544% with the addition of piperine.

- Source: https://www.ncbi.nlm...pubmed/21714124


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