The bioavailability and distribution of trans-resveratrol are constrained by ABC transporters

Planas, Joana M.; Alfaras, Irene; Colom, Helena; Juan, M. Emília

doi:10.1016/j.abb.2012.06.004

Cited by 101 publications

(83 citation statements)

References 62 publications

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“…As recently reviewed by Planas et al [309], the bioavailability and distribution of RES are constrained by ABC transporters [250,310,311]. Enterocytes rapidly metabolize RES to yield glucuronide and sulfate derivatives, which are excreted through the ABC membrane proteins.…”

Section: Potential Clinical Effects Vs Human Evidencementioning

confidence: 99%

Resveratrol and Clinical Trials: The Crossroad from In Vitro Studies to Human Evidence

Tomé‐Carneiro

Larrosa²,

González‐Sarrías

et al. 2013

CPD

397

294

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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.

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Section: Potential Clinical Effects Vs Human Evidencementioning

confidence: 99%

Resveratrol and Clinical Trials: The Crossroad from In Vitro Studies to Human Evidence

Tomé‐Carneiro

Larrosa²,

González‐Sarrías

et al. 2013

CPD

397

294

View full text Add to dashboard Cite

show abstract

“…Resveratrol and associated monoconjugates are substrates for several transporters, including BCRP, MRP (multidrug resistance-associated protein) 2, and MRP3 (Alfaras et al, 2010;Planas et al, 2012;van de Wetering et al, 2009). Modulation of transporter activity by resveratrol has been examined using various cell lines.…”

Section: Case Study: Milk Thistlementioning

confidence: 99%

Herb–Drug Interactions: Challenges and Opportunities for Improved Predictions

et al. 2013

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Supported by a usage history that predates written records and the perception that "natural" ensures safety, herbal products have increasingly been incorporated into Western health care. Consumers often self-administer these products concomitantly with conventional medications without informing their health care provider(s). Such herb-drug combinations can produce untoward effects when the herbal product perturbs the activity of drug metabolizing enzymes and/or transporters. Despite increasing recognition of these types of herb-drug interactions, a standard system for interaction prediction and evaluation is nonexistent. Consequently, the mechanisms underlying herb-drug interactions remain an understudied area of pharmacotherapy. Evaluation of herbal product interaction liability is challenging due to variability in herbal product composition, uncertainty of the causative constituents, and often scant knowledge of causative constituent pharmacokinetics. These limitations are confounded further by the varying perspectives concerning herbal product regulation. Systematic evaluation of herbal product drug interaction liability, as is routine for new drugs under development, necessitates identifying individual constituents from herbal products and characterizing the interaction potential of such constituents. Integration of this information into in silico models that estimate the pharmacokinetics of individual constituents should facilitate prospective identification of herb-drug interactions. These concepts are highlighted with the exemplar herbal products milk thistle and resveratrol. Implementation of this methodology should help provide definitive information to both consumers and clinicians about the risk of adding herbal products to conventional pharmacotherapeutic regimens.

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“…Indeed, the modifications just mentioned have been long recognized and studied for representative members of this huge family of natural compounds, including resveratrol, which is of specific interest here. Rapid glucuronidation and sulfation in enterocytes, hepatocytes, and other cells (e.g., [14][15][16][17][18][19][20][21]) and re-export to the intestinal lumen by MDR proteins [15,22,23], or possibly OATPs [24], are thought to limit the potential impact of this celebrated "natural drug" in vivo. This is a pity, given the pleiotropic effects this dietary compound is reported to have in important pathophysiological respects (for recent reviews see, e.g., [25][26][27][28][29][30]).…”

Section: Introductionmentioning

confidence: 99%

N-Monosubstituted Methoxy-oligo(ethylene glycol) Carbamate Ester Prodrugs of Resveratrol

et al. 2015

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Abstract:Resveratrol is a natural polyphenol with many interesting biological activities. Its pharmacological exploitation in vivo is, however, hindered by its rapid elimination via phase II conjugative metabolism at the intestinal and, most importantly, hepatic levels. One approach to bypass this problem relies on prodrugs. We report here the synthesis, characterization, hydrolysis, and in vivo pharmacokinetic behavior of resveratrol prodrugs in which the OH groups are engaged in an N-monosubstituted carbamate ester linkage. As promoiety, methoxy-oligo(ethylene glycol) groups (m-OEG) (CH3-[OCH2CH2]n-) of defined chain length (n = 3, 4, 6) were used. These are expected to modulate the chemico-physical properties of the resulting derivatives, much like longer poly(ethylene glycol) (PEG) chains, while retaining a relatively low MW and, thus, a favorable drug loading capacity. Intragastric administration to rats resulted in the appearance in the bloodstream of the prodrug and of the products of its partial hydrolysis, confirming protection from first-pass metabolism during absorption.

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The bioavailability and distribution of trans-resveratrol are constrained by ABC transporters

Cited by 101 publications

References 62 publications

Resveratrol and Clinical Trials: The Crossroad from In Vitro Studies to Human Evidence

Resveratrol and Clinical Trials: The Crossroad from In Vitro Studies to Human Evidence

Herb–Drug Interactions: Challenges and Opportunities for Improved Predictions

N-Monosubstituted Methoxy-oligo(ethylene glycol) Carbamate Ester Prodrugs of Resveratrol

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