Analytical method development for synthesized conjugated metabolites of trans-resveratrol, and application to pharmacokinetic studies

Iwuchukwu, Otito F.; Sharan, Satish; Canney, Daniel J.; Nagar, Swati

doi:10.1016/j.jpba.2011.12.006

Cited by 17 publications

(20 citation statements)

References 31 publications

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“…RES is known to be extensively metabolized into its conjugates, mainly R3G and R3S (Yu et al, 2002;Meng et al, 2004;Hoshino et al, 2010;Iwuchukwu et al, 2012). Lungs are the third in a series of three potential biotransformation sites (along with the gut and liver) that orally ingested RES must cross before entering the general circulation.…”

Section: Discussionmentioning

confidence: 99%

“…The absence of pulmonary glucuronidation in human lung compared with extensive pulmonary glucuronidation in mouse lungs is a possible reason for the observed difference in the pharmacokinetics of RES in rodents versus humans. In rodents, R3G has been observed as the quantitatively major metabolite (Juan et al, 2010b;Colom et al, 2011;Iwuchukwu et al, 2012;Sharan et al, 2012) compared with R3S in humans (Boocock et al, 2007;Brown et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

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Pulmonary Metabolism of Resveratrol: In Vitro and In Vivo Evidence

Sharan¹,

Nagar²

2013

Drug Metab Dispos

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The role of pulmonary metabolism in trans-resveratrol (RES) pharmacokinetics was studied in a mouse model. Plasma concentrations of RES and its major metabolites trans-resveratrol-3-sulfate (R3S) and trans-resveratrol-3-glucuronide (R3G) were compared after administration of RES by intravenous (IV) and intra-arterial (IA) routes. Total area under the curve (AUC) of RES decreased by approximately 50% when RES was administered by the IV route compared with the IA route. The AUC of R3G was also significantly higher in mice administered RES by the IV route compared with the IA route. In vitro studies performed with mouse and human lung fractions confirmed pulmonary metabolism of RES. Interestingly, mouse-lung fractions gave rise to both R3S and R3G, whereas human lung fractions yielded R3S. This indicates marked interspecies variation in RES conjugation, especially in the context of extrapolating rodent data to humans. Taken together, the results presented here underline, for the first time, the impact of pulmonary metabolism on resveratrol pharmacokinetics and interspecies differences in RES pulmonary metabolism.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pulmonary Metabolism of Resveratrol: In Vitro and In Vivo Evidence

Sharan¹,

Nagar²

2013

Drug Metab Dispos

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“…RES is extensively metabolized into its sulfated and glucuronidated metabolites, with trans-resveratrol-3-sulfate (R3S) and trans-resveratrol-3-glucuronide (R3G) as major metabolites (Juan et al, 2010;Iwuchukwu et al, 2012;Sharan et al, 2012). RES is sulfated mainly by SULT1A1 with minor contribution from SULT1E1 (Ung and Nagar, 2007).…”

Section: Pulmonary Metabolism Of Resveratrol: In Vitro and In Vivomentioning

confidence: 99%

“Target-Site” Drug Metabolism and Transport

et al. 2015

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The recent symposium on "Target-Site" Drug Metabolism and Transport that was sponsored by the American Society for Pharmacology and Experimental Therapeutics at the 2014 Experimental Biology meeting in San Diego is summarized in this report. Emerging evidence has demonstrated that drug-metabolizing enzyme and transporter activity at the site of therapeutic action can affect the efficacy, safety, and metabolic properties of a given drug, with potential outcomes including altered dosing regimens, stricter exclusion criteria, or even the failure of a new chemical entity in clinical trials. Drug metabolism within the brain, for example, can contribute to metabolic activation of therapeutic drugs such as codeine as well as the elimination of potential neurotoxins in the brain. Similarly, the activity of oxidative and conjugative drug-metabolizing enzymes in the lung can have an effect on the efficacy of compounds such as resveratrol. In addition to metabolism, the active transport of compounds into or away from the site of action can also influence the outcome of a given therapeutic regimen or disease progression. For example, organic anion transporter 3 is involved in the initiation of pancreatic b-cell dysfunction and may have a role in how uremic toxins enter pancreatic b-cells and ultimately contribute to the pathogenesis of gestational diabetes. Finally, it is likely that a combination of target-specific metabolism and cellular internalization may have a significant role in determining the pharmacokinetics and efficacy of antibody-drug conjugates, a finding which has resulted in the development of a host of new analytical methods that are now used for characterizing the metabolism and disposition of antibody-drug conjugates. Taken together, the research summarized herein can provide for an increased understanding of potential barriers to drug efficacy and allow for a more rational approach for developing safe and effective therapeutics.

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“…7) However, trans-resveratrol application in clinic is scare due to its poor water-solubility, short half-life of 109 min, 8) and undesirable oral bioavailability. 9) In vivo, RES quickly conjugated with endogenous glucose acid or sulfuric acid at 3-position to convert into the metabolites, 3-monoglucuronide and 3-monosulfate.…”

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confidence: 99%

“…9) In vivo, RES quickly conjugated with endogenous glucose acid or sulfuric acid at 3-position to convert into the metabolites, 3-monoglucuronide and 3-monosulfate. 8) Strategies regarding innovative formulations have to be under consideration to overcome shortages of RES.…”

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confidence: 99%

Pomegranate Seed Oil Exerts Synergistic Effects with <i>trans</i>-Resveratrol in a Self-nanoemulsifying Drug Delivery System

Liu

Zhang

et al. 2015

Biological & Pharmaceutical Bulletin

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Pomegranate seed oil (PSO) has diverse bioactivities. It was hyphothesized that if PSO were employed to construct a trans-resveratrol-loaded self-nanoemulsifying drug delivery system (RES SNEDDS-PSO), not only could PSO serve as an oil phase but also exert synergistic effects with resveratrol to yield better therapeutic outcomes. In this study, we prepared RES SNEDDS-PSO for the first time to validate that hypothesis. The anti-inflammatory and anticancer activities of RES SNEDDS-PSO were compared with another SNEDDS composed of oil phase isopropyl palmitate (RES SNEDDS-IP). The results showed that upon exposure to a 10-fold amount of water, RES SNEDDS-PSO was converted into nanoemulsions with a mean size of 44 nm. Nanoemulsions enhanced the water solubility of resveratrol by 20-fold, significantly improved resveratrol stability in intestinal fluid, and slowed the decomposition of resveratrol in water by 1-fold. An in vivo anti-infection test showed that the degree of inflammatory swelling in mice given RES SNEDDS-PSO was only 60 and 76% that of the group fed with RES SNEDDS-IP at doses of 10 and 20 mg/kg, respectively. An in vitro anticancer study showed that the inhibitory rate of RES SNEDDS-PSO against MCF-7 breast cancer cells was 2.03-and 1.24-fold that of RES SNEDDS-IP at a concentration of 12.5 and 25 µg/mL, respectively. This study demonstrated that the newly developed SNEDDS may be a prospective formulation in the functional food and clinical fields.Key words pomegranate seed oil; self-nanoemulsification; trans-resveratrol; anti-inflammation; anticancer activity trans-Resveratrol (RES), a natural component, possesses broad therapeutic activities in the treatment of cancer, 1,2) inflammation, 3,4) neurodegenerative disorders, 5) hyperlipemia, 6) and so on. 7) However, trans-resveratrol application in clinic is scare due to its poor water-solubility, short half-life of 109 min, 8) and undesirable oral bioavailability. 9) In vivo, RES quickly conjugated with endogenous glucose acid or sulfuric acid at 3-position to convert into the metabolites, 3-monoglucuronide and 3-monosulfate.8) Strategies regarding innovative formulations have to be under consideration to overcome shortages of RES.Self-nanoemulsifying drug delivery system (SNEDDS) may be a promising vehicle to ameliorate oral bioavailability of RES. SNEDDS is a transparent, thermodynamically stable system, usually composed of oil, surfactant, and co-solvent. It rapidly forms oil in water (o/w) nanoemulsions when diluted with gastrointestinal (GI) fluid. 10) As SNEDDS has nano size and much larger surface area, it is able to notably enhance the dissolution of drug. High surface area of nanoemulsions also provides better interaction between drug and GI fluid, resulting in improved absorption as well as bioavailability.11) Long chain triglycerides, capryol 90, labrafac PG, and so on, are often employed as oil phases of SNEDDS.12) Though those oil phases are excellent candidates to produce SNEDDS in line with treatment requirements, owing to the lack of bi...

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Analytical method development for synthesized conjugated metabolites of trans-resveratrol, and application to pharmacokinetic studies

Cited by 17 publications

References 31 publications

Pulmonary Metabolism of Resveratrol: In Vitro and In Vivo Evidence

Pulmonary Metabolism of Resveratrol: In Vitro and In Vivo Evidence

“Target-Site” Drug Metabolism and Transport

Pomegranate Seed Oil Exerts Synergistic Effects with <i>trans</i>-Resveratrol in a Self-nanoemulsifying Drug Delivery System

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