(high abosption but low bioavailability of oral resveratrol in humans, 2004)
(using 25mg per 70kg)Humans -Serum Peak <22 nM
metabolism and disposition of Resveratrol in Rats, extent of absorption, glucoronidation, and enterophatic circulation, 2002)
(using 50mg/kg of bodyweight) Rats -Serum Peak <6.6 µM
(Pharmacokinetics in mice and growth inhibitory properties of putative cancer chemopreventative agent resveratrol and synthetic analogue trans, 2004)
(using 240mg/kg of bodyweight) Mouse -Serum Peak <32 µM
Using these numbers, plus the study below, where humans given 71mg/kg (assuming 70kg body wt. with 5gm oral resv) had a serum peak of 2.4 µM, we can look at the serum levels obtained per 1mg/kg dose.
6.6uM/50mg kg(-1) = 0.132 (rat)
32 uM/240mg kg(-1) = 0.133 (mouse)
0.022 uM/0.357 mg kg(-1) = 0.0616 (human low dose)
2.4 uM/71mg kg(-1) = 0.0338 (human high dose)
I consider the human high dose number to be more reliable due to the larger values involved, Boocock's involvement in development of resveratrol quantitation methodology, and the fact that the 22 nM value (from Walle et al., Drug Metab Dispos. 2004 Dec;32(12):1377-82.) was given as an upper limit. I wish that I had the full paper from Boocock et al., because then I'd feel comfortable comparing the high and low dose numbers to see if there is a "swamping" effect. Rat and mouse are certainly consistent here, though they are both at high dose levels. For the time being I'll just compare the rat and human high dose numbers:
0.132/0.0338 = 3.9
Edit 7-09-08: This ratio is too high because the rat and mouse data above uses formulations that enhance bioavailability, while the human data does not. A more correct ratio is 1.3. For more explanation, see this post.So it looks like the factor of six that is sometimes used to compare doses between mice and men works in reverse in the case of resveratrol. We don't need
one sixth of the dose, but rather something on the order of
two to four times one half to two times as much, if we wish to reach plasma levels comparable to the mice.
Cancer Epidemiol Biomarkers Prev. 2007 Jun;16(6):1246-52.
Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent.
Boocock DJ, Faust GE, Patel KR, Schinas AM, Brown VA, Ducharme MP, Booth TD, Crowell JA, Perloff M, Gescher AJ, Steward WP, Brenner DE.
The red grape constituent resveratrol possesses cancer chemopreventive properties in rodents. The hypothesis was tested that, in healthy humans, p.o. administration of resveratrol is safe and results in measurable plasma levels of resveratrol. A phase I study of oral resveratrol (single doses of 0.5, 1, 2.5, or 5 g) was conducted in 10 healthy volunteers per dose level. Resveratrol and its metabolites were identified in plasma and urine by high-performance liquid chromatography-tandem mass spectrometry and quantitated by high-performance liquid chromatography-UV. Consumption of resveratrol did not cause serious adverse events. Resveratrol and six metabolites were recovered from plasma and urine. Peak plasma levels of resveratrol at the highest dose were 539 +/- 384 ng/mL (2.4 mumol/L, mean +/- SD; n = 10), which occurred 1.5 h post-dose. Peak levels of two monoglucuronides and resveratrol-3-sulfate were 3- to 8-fold higher. The area under the plasma concentration curve (AUC) values for resveratrol-3-sulfate and resveratrol monoglucuronides were up to 23 times greater than those of resveratrol. Urinary excretion of resveratrol and its metabolites was rapid, with 77% of all urinary agent-derived species excreted within 4 h after the lowest dose. Cancer chemopreventive effects of resveratrol in cells in vitro require levels of at least 5 mumol/L. The results presented here intimate that consumption of high-dose resveratrol might be insufficient to elicit systemic levels commensurate with cancer chemopreventive efficacy. However, the high systemic levels of resveratrol conjugate metabolites suggest that their cancer chemopreventive properties warrant investigation. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1246-52).
PMID: 17548692
Edited by niner, 09 July 2008 - 05:45 AM.