Dataset Information

In vivo-formed versus preformed metabolite kinetics of trans-resveratrol-3-sulfate and trans-resveratrol-3-glucuronide.

ABSTRACT: Metabolites in safety testing have gained a lot of attention recently. Regulatory agencies have suggested that the kinetics of preformed and in vivo-formed metabolites are comparable. This subject has been a topic of debate. We have compared the kinetics of in vivo-formed with preformed metabolites. trans-3,5,4'-Trihydroxystilbene [trans-resveratrol (RES)] and its two major metabolites, resveratrol-3-sulfate (R3S) and resveratrol-3-glucuronide (R3G) were used as model substrates. The pharmacokinetics (PK) of R3S and R3G were characterized under two situations. First, the pharmacokinetics of R3S and R3G were characterized (in vivo-formed metabolite) after administration of RES. Then, synthetic R3S and R3G were administered (preformed metabolite) and their pharmacokinetics were characterized. PK models were developed to describe the data. A three-compartment model for RES, a two-compartment model for R3S (preformed), and an enterohepatic cycling model for R3G (preformed) was found to describe the data well. These three models were further combined to build a comprehensive PK model, which was used to perform simulations to predict in vivo-formed metabolite kinetics. Comparisons were made between in vivo-formed and preformed metabolite kinetics. Marked differences were observed in the kinetics of preformed and in vivo-formed metabolites.

SUBMITTER: Sharan S

PROVIDER: S-EPMC3463825 | biostudies-other | 2012 Oct

REPOSITORIES: biostudies-other

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In vivo-formed versus preformed metabolite kinetics of trans-resveratrol-3-sulfate and trans-resveratrol-3-glucuronide.

Sharan Satish S Iwuchukwu Otito F OF Canney Daniel J DJ Zimmerman Cheryl L CL Nagar Swati S

Drug metabolism and disposition: the biological fate of chemicals 20120717 10

Metabolites in safety testing have gained a lot of attention recently. Regulatory agencies have suggested that the kinetics of preformed and in vivo-formed metabolites are comparable. This subject has been a topic of debate. We have compared the kinetics of in vivo-formed with preformed metabolites. trans-3,5,4'-Trihydroxystilbene [trans-resveratrol (RES)] and its two major metabolites, resveratrol-3-sulfate (R3S) and resveratrol-3-glucuronide (R3G) were used as model substrates. The pharmacokin ...[more]

PMID: 22807110

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Project description:Resveratrol has been reported to inhibit or induce DNA damage, depending upon the type of cell and the experimental conditions. Dietary resveratrol is present in the body predominantly as metabolites and limited data is available concerning the activities of these metabolic products. In the present study, physiologically obtainable levels of the resveratrol metabolites resveratrol-3-O-glucuronide, resveratrol-4'-O-glucuronide and resveratrol-3-O-sulfate were evaluated for their ability to protect Jurkat T cells against DNA damage induced by the topoisomerase I inhibitors camptothecin and topotecan. The cells were pretreated for 24 h with 10 µM resveratrol aglycone or each resveratrol metabolite prior to the induction of DNA damage with camptothecin or topotecan. In separate experiments, the cells were co-treated with resveratrol or its metabolites, and a topoisomerase I inhibitor. The detection of histone 2AX phosphorylation and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) were used to determine DNA damage, and apoptosis was measured using an antibody against cleaved poly ADP-ribose polymerase. It was identified that pretreatment of the cells with resveratrol-3-O-glucuronide and resveratrol-4'-O-glucuronide reduced the mean fluorescence intensity of staining for DNA strand breaks following treatment with camptothecin, while the percentage of cells undergoing apoptosis was unchanged. However, pretreatment of the cells with resveratrol aglycone increased the DNA damage and apoptosis induced by the drugs. These results suggest that the glucuronide metabolites of resveratrol partially protected the cells from DNA damage, but did not influence the induction of cell death by camptothecin and topotecan. These data suggest that resveratrol aglycone treatment may be beneficial for treating types of cancer that have direct contact with resveratrol prior to its metabolism, including gastrointestinal cancers, which are routinely treated with topoisomerase I inhibitors.

Project description:BackgroundGuidelines in pediatric restorative dentistry recommend the use of preformed pediatric stainless steel crowns (SSCs) in cases of severe tooth decay of at least two surfaces. This clinically effective and safe restorative option is frequently refused by parents for esthetic reasons; they prefer conventional restorations using esthetic filling materials (composites, glass ionomer) if lesion severity limited to two surfaces permits. Recently, manufacturers have proposed esthetic preformed pediatric zirconia crowns (ZCs) but these have been assessed in only two randomized clinical trials (RCT) with follow-ups of 6 and 12 months. Only one of these RCTs was carried out on primary molars to test ZCs (NuSmile ZR) without a groove in its inner surface. The primary objective of this proposed RCT is to assess the effectiveness of ZCs compared with SSCs. Our hypothesis is that the effectiveness of ZCs will be equivalent to that of SSCs.MethodsIn this split-mouth, 2-year RCT, pairs of primary molars in 101 child participants will be randomized and restored with SSCs (ESPE, 3M) and ZCs (EZCrowns, Sprig Oral Health Technologies) characterized by grooves on their inner surface. Primary molars will first be allocated to SSCs, and 1 to 2 weeks later the other primary molar of the same pair will be restored by ZC. The primary outcome is the success defined by the "absence of major clinical and radiographic failure" (e.g., pain, pulp infection, dental abscess or periradicular pathology visible on radiographs). The secondary outcomes include the retention and fracture rates, the gingival condition, the wear of the antagonist of the treated teeth, as well as both parental and child satisfaction.DiscussionThis study will investigate two types of preformed pediatric crowns for the management of severe decay on primary molars. The results may help practitioners choose the better therapeutic option and to explain to parents the advantages and disadvantages of these two therapies.Trial registrationNCT03296709 . Registered on 27 September 2017.

Dataset Information

In vivo-formed versus preformed metabolite kinetics of trans-resveratrol-3-sulfate and trans-resveratrol-3-glucuronide.

Publications

In vivo-formed versus preformed metabolite kinetics of trans-resveratrol-3-sulfate and trans-resveratrol-3-glucuronide.

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