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Journal ArticleDOI

Enhancing the bioavailability of resveratrol by combining it with piperine.

TL;DR: Piperine significantly improves the in vivo bioavailability of resveratrol through inhibiting its glucuronidation, thereby slowing its elimination and further detailed research is needed to study the mechanism of improved bioavailability via its combination with piperine.
Abstract: Scope Resveratrol (3,5,4'-trihydroxystilbene) is a phytoalexin shown to possess a multitude of health-promoting properties in pre-clinical studies. However, the poor in vivo bioavailability of resveratrol due to its rapid metabolism is being considered as a major obstacle in translating its effects in humans. In this study, we examined the hypothesis that piperine will enhance the pharmacokinetic parameters of resveratrol via inhibiting its glucuronidation, thereby slowing its elimination. Methods and results Employing a standardized LC/MS assay, we determined the effect of piperine co-administration with resveratrol on serum levels resveratrol and resveratrol-3-O-β-D-glucuronide in C57BL mice. 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. Conclusion Our study demonstrated that piperine significantly improves the in vivo bioavailability of resveratrol. However, further detailed research is needed to study the mechanism of improved bioavailability of resveratrol via its combination with piperine as well as its effect on resveratrol metabolism.

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Citations
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Journal ArticleDOI
TL;DR: An increasing number of recent studies have aimed at designing novel resveratrol formulations to overcome its poor solubility, limited stability, high metabolization and weak bioavailability, which is a barrier to the development of therapeutic applications.

509 citations


Cites methods from "Enhancing the bioavailability of re..."

  • ...[88] used piperine, an alkaloid derived from black pepper, in vivo to inhibit glucuronidation, and observed a 1544% increase in the maximum serum resveratrol concentration, a 229% enhancement of the area under the concentration curve expressing the degree of exposure to resveratrol, and a two-fold increase in Tmax after single oral administration in healthy mice....

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Journal ArticleDOI
TL;DR: The current focus of this review is resveratrol’s in vivo and in vitro effects in a variety of cancers, and intracellular molecular targets modulated by this polyphenol.
Abstract: Natural product compounds have recently attracted significant attention from the scientific community for their potent effects against inflammation-driven diseases, including cancer. A significant amount of research, including preclinical, clinical, and epidemiological studies, has indicated that dietary consumption of polyphenols, found at high levels in cereals, pulses, vegetables, and fruits, may prevent the evolution of an array of diseases, including cancer. Cancer development is a carefully orchestrated progression where normal cells acquires mutations in their genetic makeup, which cause the cells to continuously grow, colonize, and metastasize to other organs such as the liver, lungs, colon, and brain. Compounds that modulate these oncogenic processes can be considered as potential anti-cancer agents that may ultimately make it to clinical application. Resveratrol, a natural stilbene and a non-flavonoid polyphenol, is a phytoestrogen that possesses anti-oxidant, anti-inflammatory, cardioprotective, and anti-cancer properties. It has been reported that resveratrol can reverse multidrug resistance in cancer cells, and, when used in combination with clinically used drugs, it can sensitize cancer cells to standard chemotherapeutic agents. Several novel analogs of resveratrol have been developed with improved anti-cancer activity, bioavailability, and pharmacokinetic profile. The current focus of this review is resveratrol's in vivo and in vitro effects in a variety of cancers, and intracellular molecular targets modulated by this polyphenol. This is also accompanied by a comprehensive update of the various clinical trials that have demonstrated it to be a promising therapeutic and chemopreventive agent.

459 citations


Cites background from "Enhancing the bioavailability of re..."

  • ...Resveratrol’s poor bioavailability is a significant issue with regard to extrapolating its effects to humans, and various approaches have been created to enhance its bioavailability [311], including consuming it with various foods [312], using it in combination with an additional phytochemical piperine [313], and using a prodrug approach [314], micronized powders [315,316], or nanotechnological formulations [317–319]....

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Journal ArticleDOI
TL;DR: This review highlights the in vivo effects of resveratrol treatment on breast, colorectal, liver, pancreatic, and prostate cancers and suggests that many factors need to be considered before resver atrol can be used for human cancer prevention or therapy.
Abstract: Resveratrol is a naturally occurring polyphenol that provides a number of anti-aging health benefits including improved metabolism, cardioprotection, and cancer prevention. Much of the work on resveratrol and cancer comes from in vitro studies looking at resveratrol actions on cancer cells and pathways. There are, however, comparatively fewer studies that have investigated resveratrol treatment and cancer outcomes in vivo, perhaps limited by its poor bioavailability when taken orally. Although research in cell culture has shown promising and positive effects of resveratrol, evidence from rodents and humans is inconsistent. This review highlights the in vivo effects of resveratrol treatment on breast, colorectal, liver, pancreatic, and prostate cancers. Resveratrol supplementation in animal models of cancer has shown positive, neutral as well as negative outcomes depending on resveratrol route of administration, dose, tumor model, species, and other factors. Within a specific cancer type, there is variability between studies with respect to strain, age, and sex of animal used, timing and method of resveratrol supplementation, and dose of resveratrol used to study cancer endpoints. Together, the data suggest that many factors need to be considered before resveratrol can be used for human cancer prevention or therapy.

422 citations


Cites background from "Enhancing the bioavailability of re..."

  • ...In mice, piperine significantly increased the serum levels of resveratrol after oral administration of both compounds (Johnson et al. 2011)....

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Journal ArticleDOI
TL;DR: This review will focus on the currently available evidence regarding resveratrol’s effects on humans obtained from randomized clinical trials and provide a critical outlook for further research on this molecule that is evolving from a minor dietary compound to a possible multi-target therapeutic drug.
Abstract: Resveratrol (3,5,4’-trihydroxy-trans-stilbene) is a non-flavonoid polyphenol that may be present in a limited number of food-stuffs such as grapes and red wine. Resveratrol has been reported to exert a plethora of health benefits through many different mechanisms of action. This versatility and presence in the human diet have drawn the worldwide attention of many research groups over the past twenty years, which has resulted in a huge output of in vitro and animal (preclinical) studies. In line with this expectation, many resveratrol-based nutraceuticals are consumed all over the world with questionable clinical/scientific support. In fact, the confirmation of these benefits in humans through randomized clinical trials is still very limited. The vast majority of preclinical studies have been performed using assay conditions with a questionable extrapolation to humans, i.e. too high concentrations with potential safety concerns (adverse effects and drug interactions), short-term exposures, in vitro tests carried out with non-physiological metabolites and/or concentrations, etc. Unfortunately, all these hypothesis-generating studies have contributed to increased the number of ‘potential’ benefits and mechanisms of resveratrol but confirmation in humans is very limited. Therefore, there are many issues that should be addressed to avoid an apparent endless loop in resveratrol research. The so-called ‘Resveratrol Paradox’, i.e., low bioavailability but high bioactivity, is a conundrum not yet solved in which the final responsible actor (if any) for the exerted effects has not yet been unequivocally identified. It is becoming evident that resveratrol exerts cardioprotective benefits through the improvement of inflammatory markers, atherogenic profile, glucose metabolism and endothelial function. However, safety concerns remain unsolved regarding chronic consumption of high RES doses, specially in medicated people. This review will focus on the currently available evidence regarding resveratrol’s effects on humans obtained from randomized clinical trials. In addition, we will provide a critical outlook for further research on this molecule that is evolving from a minor dietary compound to a possible multi-target therapeutic drug.

391 citations


Cites background from "Enhancing the bioavailability of re..."

  • ...Other more specific strategies previously approached in animals such as the inhibition of CYPs by using known inhibitors like piperine [320] are also under evaluation in humans (Supplementary Table 11)....

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Journal ArticleDOI
TL;DR: The data regarding select phytochemicals including curcumin, resveratrol, lycopene, folates and tea polyphenols are summarized with emphasis on the clinical evidence supporting the efficacy of these compounds in high-risk populations.
Abstract: // Ritesh Kotecha 1 , Akiyoshi Takami 2 and J. Luis Espinoza 3 1 Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States of America 2 Department of Internal Medicine, Division of Hematology, Aichi Medical University, School of Medicine, Nagakute, Aichi, Japan 3 Department of Hematology Oncology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan Correspondence to: J. Luis Espinoza, email: // Keywords : cancer chemoprevention, phytochemicals, resveratrol, curcumin, antioxidants Received : December 30, 2015 Accepted : May 12, 2016 Published : May 25, 2016 Abstract Cancer chemoprevention involves the use of different natural or biologic agents to inhibit or reverse tumor growth. Epidemiological and pre-clinical data suggest that various natural phytochemicals and dietary compounds possess chemopreventive properties, and in-vitro and animal studies support that these compounds may modulate signaling pathways involved in cell proliferation and apoptosis in transformed cells, enhance the host immune system and sensitize malignant cells to cytotoxic agents. Despite promising results from experimental studies, only a limited number of these compounds have been tested in clinical trials and have shown variable results. In this review, we summarize the data regarding select phytochemicals including curcumin, resveratrol, lycopene, folates and tea polyphenols with emphasis on the clinical evidence supporting the efficacy of these compounds in high-risk populations.

283 citations


Cites background or result from "Enhancing the bioavailability of re..."

  • ...This conclusion was further validated after Zheng and colleagues in a study of prostate cancer in the Asian population [59]....

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  • ...Pharmacokinetic evidence indicate that resveratrol has poor bioavailability due to its rapid and extensive liver metabolism which severely impairs its therapeutic effects [58, 59]....

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  • ...Several approaches, with variable results, have been attempted to overcome this problem [60], including combining resveratrol with glucuronidation inhibitors such as piperine [59], developing resveratrol nanoparticles [61, 62], and utilizing novel drug delivery systems to protect and stabilize resveratrol to enhance its bioavailability [63, 64]....

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References
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Journal ArticleDOI
TL;DR: A comprehensive and critical review of the in vivo data on resveratrol is provided, and its potential as a therapeutic for humans is considered.
Abstract: Resveratrol, a constituent of red wine, has long been suspected to have cardioprotective effects. Interest in this compound has been renewed in recent years, first from its identification as a chemopreventive agent for skin cancer, and subsequently from reports that it activates sirtuin deacetylases and extends the lifespans of lower organisms. Despite scepticism concerning its bioavailability, a growing body of in vivo evidence indicates that resveratrol has protective effects in rodent models of stress and disease. Here, we provide a comprehensive and critical review of the in vivo data on resveratrol, and consider its potential as a therapeutic for humans.

3,509 citations

Journal ArticleDOI
TL;DR: Data from Caerphilly, Wales, show that platelet aggregation, which is related to CHD, is inhibited significantly by alcohol at levels of intake associated with reduced risk of CHD.

3,489 citations


"Enhancing the bioavailability of re..." refers background in this paper

  • ...The phenomenon of ‘‘French Paradox’’, the observation that French people suffer a relatively low incidence of coronary heart disease (despite having a diet relatively rich in saturated fats), has been attributed to the consumption of red wine that contains resveratrol [6]....

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Journal ArticleDOI
TL;DR: The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects.
Abstract: The medicinal properties of curcumin obtained from Curcuma longa L. cannot be utilised because of poor bioavailability due to its rapid metabolism in the liver and intestinal wall. In this study, the effect of combining piperine, a known inhibitor of hepatic and intestinal glucuronidation, was evaluated on the bioavailability of curcumin in rats and healthy human volunteers. When curcumin was given alone, in the dose 2 g/kg to rats, moderate serum concentrations were achieved over a period of 4 h. Concomitant administration of piperine 20 mg/kg increased the serum concentration of curcumin for a short period of 1-2 h post drug. Time to maximum was significantly increased (P < 0.02) while elimination half life and clearance significantly decreased (P < 0.02), and the bioavailability was increased by 154%. On the other hand in humans after a dose of 2 g curcumin alone, serum levels were either undetectable or very low. Concomitant administration of piperine 20 mg produced much higher concentrations from 0.25 to 1 h post drug (P < 0.01 at 0.25 and 0.5 h; P < 0.001 at 1 h), the increase in bioavailability was 2000%. The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects.

1,599 citations

Journal ArticleDOI
TL;DR: The dietary polyphenol resveratrol has been shown to have chemopreventive activity against cardiovascular disease and a variety of cancers in model systems, but it is not clear whether the drug reaches the proposed sites of action in vivo after oral ingestion, especially in humans.
Abstract: The dietary polyphenol resveratrol has been shown to have chemopreventive activity against cardiovascular disease and a variety of cancers in model systems, but it is not clear whether the drug reaches the proposed sites of action in vivo after oral ingestion, especially in humans. In this study, we examined the absorption, bioavailability, and metabolism of 14C-resveratrol after oral and i.v. doses in six human volunteers. The absorption of a dietary relevant 25-mg oral dose was at least 70%, with peak plasma levels of resveratrol and metabolites of 491 +/- 90 ng/ml (about 2 microM) and a plasma half-life of 9.2 +/- 0.6 h. However, only trace amounts of unchanged resveratrol (<5 ng/ml) could be detected in plasma. Most of the oral dose was recovered in urine, and liquid chromatography/mass spectrometry analysis identified three metabolic pathways, i.e., sulfate and glucuronic acid conjugation of the phenolic groups and, interestingly, hydrogenation of the aliphatic double bond, the latter likely produced by the intestinal microflora. Extremely rapid sulfate conjugation by the intestine/liver appears to be the rate-limiting step in resveratrol's bioavailability. Although the systemic bioavailability of resveratrol is very low, accumulation of resveratrol in epithelial cells along the aerodigestive tract and potentially active resveratrol metabolites may still produce cancer-preventive and other effects.

1,577 citations


"Enhancing the bioavailability of re..." refers background in this paper

  • ...Interestingly, in our study, we observed the presence of a second peak in serum with the resveratrol metabolite, which may be explained by enterohepatic recirculation of resveratrol, which has been observed in rats and humans [20, 27]....

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  • ...Studies in healthy human volunteers have shown that resveratrol is rapidly absorbed but quickly metabolized, usually within 30–60 min following oral or intravenous administration in humans [10, 20]....

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Journal ArticleDOI
TL;DR: The PKSolver provided pharmacokinetic researchers with a fast and easy-to-use tool for routine and basic PK and PD data analysis with a more user-friendly interface and its output could be generated in Microsoft Word in the form of an integrated report.

1,493 citations