This trial represents the first description of pharmacokinetic parameters for resveratrol after ingestion of SRT501, micronized resveratrol, in subjects with colorectal cancer. The dose of resveratrol employed (5.0 g) is equivalent to one of the dose levels at which non-micronized resveratrol was recently administered to healthy volunteers [9
]. In the healthy volunteer study, ten subjects on 5.0 g of the non-micronized resveratrol reported twenty AEs possibly or probably related to ingestion of resveratrol capsules, which compares with seventeen AEs reported for six patients who received SRT501. The two formulations therefore seem to cause a similar incidence of AEs, although in the previous study non-micronized resveratrol was administered for a longer duration (29 days) than SRT501. All AEs reported following SRT501 administration were mild, whilst two of the ten healthy volunteers on non-micronized resveratrol, presented with moderate and one with severe gastrointestinal AEs [9
]. This comparison provides the possibility that SRT501 formulated as a suspension may be better tolerated than non-micronized resveratrol given as ten 0.5 g capsules per day. Since micronized resveratrol was expected to afford higher systemic concentrations [19
], this finding also suggests that ingestion of a large number of capsules or the presence of non-absorbed resveratrol in the GI tract may be responsible for the adverse effects, rather than the actual plasma concentrations achieved.
The pharmacokinetic analysis revealed that the mean plasma Cmax
for resveratrol measured after ingestion of SRT501 (mean 1942 ng/mL , CV:73.3%) was 3.6-fold higher than that achieved following a single dose of non-micronized resveratrol in healthy volunteers (mean 538.8 ng/mL (CV:72.5%) [8
], consistent with the superior bioavailability of resveratrol when administered as SRT501 compared to non-micronized agent. The time taken to reach the Cmax
for resveratrol was 2.8 h in the case of SRT501 compared to 1.5 h for non-micronized resveratrol [8
Concentrations of resveratrol achieved in hepatic metastases after administration of SRT501 (0.22-12.4 μM) were of the order of magnitude observed to elicit pharmacological effect in human colorectal cancer cells in vitro
and in pre-clinical models in vivo
. This interpretation is corroborated by the finding that SRT501 caused a small but significant increase in cleaved caspase-3 immuno-reactivity in tumor tissue, when compared to equivalent tissue from subjects on placebo. Whilst we were not able to confirm these effects via other pharmacodynamic markers, this may be due to low sensitivity of the techniques used. Mechanisms by which low concentrations of resveratrol have been observed to induce apoptotic and anti-proliferative effect in vitro
include induction of Fas redistribution and its association with the death-inducing signalling (DISC) complex [20
], and via inhibition of wnt signalling and subsequent decrease in nuclear β-catenin localisation [21
]. In a pre-clinical model of diethylnitrosamine-initiated hepatocarcinogenesis, significant resveratrol-mediated apoptosis likely resulted from increased Bax expression and consequent increase in the Bax:Bcl2 ratio [22
]. Whilst tissue resveratrol levels were not determined in this study, extrapolation of data from rodent PK studies [23
] would suggest hepatic resveratrol concentrations necessary for apoptosis induction, to be only moderately higher than the maximum achieved in the SRT501 study described here.
This is the first demonstration that resveratrol can reach potentially active concentrations in human tissues that are distant to the GI tract.
In summary, the results of this pilot study of SRT501 allow three conclusions: i. its daily consumption for 14 days seems to be well tolerated in colorectal cancer patients, ii. Cmax for SRT501 was higher than reported for equivalent dose of non-micronised resveratrol, iii. its ingestion furnished measurable resveratrol levels in a tissue distant to the GI tract (in particular the liver), and these concentrations were accompanied by a significant pharmacological effect.
Micronized resveratrol, as exemplified by SRT501, warrants further clinical exploration in larger cohorts of subjects, in order to test the hypothesis that resveratrol may be of use as a cancer chemopreventive or chemotherapeutic agent.