Resveratrol pharmacokinetics

The evaluation of pharmacokinetic analysis of resveratrol was carried out in different animal models such as rats, mice, and rabbits [Asensi et al., 2002 Chen et al., 2007 Juan et al., 2002 Marier et al., 2002 Sale et al., 2004] furthermore, pharmacokinetic analysis was also evaluated with other resveratrol derivatives such as piceid [Lv et al., 2006 Zhou et al., 2007], a Smilax china root extract [Huang et al., 2008], 3,4,5,4 -tetramethoxystilbene [Sale et al., 2004], piceatan-nol, pinosylvin, and rhapontigenin [Roupe et al., 2006] (Table 13.4). 

Another pharmacokinetic study was carried out after intravenous administration of 4.87 mg/kg of c/.v-rcsvcratrol and 5.13 mg/kg of /ruH.v-resveratrol to Sprague-Dawley rats. The study showed that both isomers showed a rapid eliminate disposition in 90 min [Chen et al., 2007],... 

There is a further pharmacokinetic study in which /ruH.v-resveratrol in the aglycone form and the glucuronide forms were examined following intravenous (15 mg/kg) and oral (50 mg/kg) administration of /rau.v-resveratrol to rats [Marier et al., 2002], After intravenous administration, the plasmatic resveratrol concentrations declined rapidly over the first 2 h. Then, concentration profiles of resveratrol and resveratrol glucuronide from intravenous or oral administration increased abruptly due to enterohepatic recirculation over the 4- to 8-h time period that resulted in a significant maintenance in the terminal elimination... 

Table 13.4 Pharmacokinetic Studies of Resveratrol in Animal Models and Humans ...

The pharmacokinetic dispositions of other stilbenes that are structurally similar to resveratrol and have pharmacological activity across many anticancer, anti-inflammatory, and antioxidant assays have been studied. The pharmacokinetics was characterized in male Sprague-Dawley rats after single intravenous... 

Recently, the pharmacokinetics of resveratrol from Smilax china, a rhizome extensively used in traditional Chinese medicine was evaluated [Huang et al., 2008]. Forty-five female rats were orally administered with 1 g/kg S. china extract equivalent to 180 mg/kg of oxyresveratrol and 80 mg/kg of resveratrol. The pharmacokinetic parameters showed that the two stilbenes were rapidly absorbed into the body fluid from the gastrointestinal tract and could still be detected in the plasma at least 6 h after the administration [Huang et al., 2008], probably due to the high dose administered. 

In 2007, Boocock et al. [2007] were the first to publish a complete phase I dose pharmacokinetic study in humans. Ten healthy volunteers were recruited to consume single doses of oral resveratrol (0.5, 1, 2.5, or 5 g). Consumption of resveratrol did not cause serious adverse events. Analyses of resveratrol and its metabolites were performed by LC-MS/MS. In plasma in all intake doses resveratrol-3-sulfate (56%) was the highest metabolite, the second and third metabolites were monoglucuronides (17 and 23%, respectively), and, finally, the lowest was free resveratrol (5%). Resveratrol was rapidly absorbed, the 7/nax for all metabolites ranged between 0.8 and 2.4 h, although the half-lives of free resveratrol and the conjugated forms remained for a long time in plasma, between 2.9 and 11.5 h. 

Boocock DJ, Faust GE, Patel KR, Schinas AM, Brown VA, Ducharme MP, Booth TD, Crowell JA, Perloff M, Gescher AJ, Steward WP, Brenner DE. 2007. Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol Biomarkers Prev 16 1246-1252. 

Chen X, He H, Wang G, Yang B, Ren W, Ma L, Yu Q. 2007. Stereospecific determination of cis- and traws-resveratrol in rat plasma by HPLC Application to pharmacokinetic studies. Biomed Chromatogr 21 257-265. 

Huang H, Zhang J, Chen G, Lu Z, Wang X, Sha N, Shao B, Li P, Guo DA. 2008. High performance liquid chromatographic method for the determination and pharmacokinetic studies of oxyresveratrol and resveratrol in rat plasma after oral administration of Smilax china extract. Biomed Chromatogr 22 421-427. 

Sale S, Verschoyle RD, Boocock D, Jones DJ, Wilsher N, Ruparelia KC, Potter GA, Farmer PB, Steward WP, Gescher AJ. 2004. Pharmacokinetics in mice and growth-inhibitory properties of the putative cancer chemopreventive agent resveratrol and the synthetic analogue trans 3,4,5,4 -tetramethoxystilbene. Br J Cancer 90 736-744. 

The effective half-life of resveratrol is reported to be relatively short. Recent work by Soleas et al. [27] indicates that, following oral administration, the concen tration of trans-resveratrol in blood and serum peaked very rapidly in rats. However, its metabolites appear to be more slowly metabolized, and 50-75% of total trarrs-resveratrol seemed to be absorbed in vivo [27]. Another group showed that plasma levels of resveratrol in rabbits, rats, and mice peaked within minutes following intravenous or oral administration (20 mg/kg) [33]. Vascular tissue levels followed plasma levels but were low. Most of the resveratrol measured was found in the trans form and was rapidly metabolized by hepatocytes [33]. In contrast, the pharmacokinetics of the aglycone and glucuronide forms of tra/rs-resveratrol were studied following intravenous or oral administration to rats. As was observed by others, plasma concentrations of resveratrol peaked and then declined rapidly however, a second increase in plasma concentration... 

A study in animals found that pretreatment with oral ciclosporin had no effect on the pharmacokinetics of alcohol or acetaldehyde. This suggests that any difference in the alcohol consumption of patients taking ciclosporin is unlikely to have a pharmacokinetic basis. The mechanism by which red wine exerts its effect is not known. White wine does not appear to affect ciclosporin pharmacokinetics," so the interaction is not believed to be an effect of alcohol. Antioxidants in red wine such as resveratrol may inactivate the cytochrome P450 isoenzyme CYP3A4 and this would also be expected to increase ciclosporin levels. The solubility of ciclosporin is decreased in red wine and it is possible that substances in red wine bind ciclosporin in the gastrointestinal tract and reduce its bioavailability. Another study by the same authors suggested that ciclosporin absorption is possibly impaired by P-glycoprotein induction. ... 

In a dose escalation study, Boocock et al. evaluated the safety and pharmacokinetics of resveratrol administered as a single dose (0.5, 1, 2.5, or 5 g) [111]. The peak plasma concentration of the parent molecule across the four dose levels ranged from 73 to 539 ng mL (0.3-2.4 pM). The authors suggest that these concentrations are markedly below the resveratrol concentration required in in vitro experiments to elicit pharmacological effects associated with cancer chemoprevention (>5 pM). The most abundant metabolites were resveratrol 3-sulfate and two resveratrol monoglucuronides, with area under the plasma concentration curve values up to 23 times greater than those of resveratrol. 

Kapetanovic, l.M, Muzzio, M., Huang, Z, Thompson, T.N. et al. (2011) Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethyl ether analog, pterostilbene, in rats. Cancer Chemother. Pharmacol, 68, 593 -601,... 

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