There's a lot to chew on here. I've generally been impressed with the level of science at AOR, yet I've also seen a level of hype and occasional scientific illiteracy on their web site that give me pause. So far I've chalked it up to a disconnect between the people in the lab and the copy writers (which is a problem in itself). At this point, I think their approach to the enhancement of resveratrol bioavailability is a mixed bag. Here's what I've come up with.
The Problem: Resveratrol's bioavailability is poor due to extensive conjugation in the liver and also in the gut. This is primarily sulfation but also glucuronidation.
Not a Problem: The absorption of resveratrol from the gut is pretty good- something like 60-70%, so it doesn't seem like much help is needed there. The resveratrol molecule is already studded with hydroxyls, so it does not need to be oxidized further by P450s; P450s are not really an issue here.
AOR's approach to improving the bioavailability of resveratrol:Quercetin: An extremely potent inhibitor of resveratrol sulfation in both liver and gut, with an IC50 of 12 and 15 picomolar, respectively. (De Santi, et al. PMID: 10923862) This makes perfect sense as an adjuvant. Why 51 mg? Sounds more "scientific" than 50 mg? (OK, I'm being cynical...)
Luteolin: There's some (weak) evidence that it's a pGp inhibitor. (pGp is Permeability GlycoProtein, a xenobiotic efflux pump. It acts to pump drugs out of your blood and back into the intestine.) PGp only works for certain compounds, and I don't think resveratrol is one of them, so luteolin probably doesn't do much there. Luteolin is also a multiple P450 inhibitor (see below). That's not going to help with resveratrol, although it might cause trouble with prescription drugs. I don't really see the point of the luteolin.
Drug Metab Dispos. 2007 Feb;35(2):185-8. Epub 2006 Nov 8.
The in vitro drug interaction potential of dietary supplements containing multiple herbal components.
Foti RS, Wahlstrom JL, Wienkers LC.
Biochemistry/Biophysics Group, Amgen Pharmacokinetics and Drug Metabolism, Seattle, Washington 98119, USA. rfoti@amgen.com
Herbal-based remedies are widely used as alternative treatments for a number of ailments. In addition, the use of products that contain both single and multiple herbal constituents is becoming increasingly common. The work described in this report examined the in vitro drug interaction potential for a commonly used herbal cold remedy reported to contain a mixture of eight herbal components. Experiments conducted in human liver microsomes exhibited significant inhibition (<10% of control activity remaining) of multiple cytochrome P450 (P450) isoforms, including CYP2B6, CYP2C9, and CYP2D6, by the herbal mixture. In an attempt to explain the observed P450 inhibition by the herbal mixture, individual active components were obtained and tested for inhibitory potency. Inhibition of multiple P450 activities by a single constituent, luteolin, was observed. Conversely, inhibition of a single isoform by several herbal components was noted for CYP2B6. Based on the data presented, it is concluded that mixtures of herbal components may exhibit multiple modes of P450 inhibition, indicating the potential for complex herbal-drug interaction scenarios to occur.
PMID: 17093003
Finally, they claim that luteolin is a more powerful inhibitor of sulphation than quercetin (and that's really saying something!) but according to the following, luteolin is not only
not an inhibitor of sulphation, but it actually
enhances glucuronidation 3-5 fold! That does not seem like what you want. Maybe resveratrol is a special case? I don't know what's up here.
Drug Metab Dispos. 2002 May;30(5):564-9.
Induction of human UDP-glucuronosyltransferase UGT1A1 by flavonoids-structural requirements.
Walle UK, Walle T.
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Recent studies in our laboratory in the human hepatic and intestinal cell lines Hep G2 and Caco-2 have demonstrated induction of UGT1A1 by the flavonoid chrysin (5,7-dihydroxyflavone) using catalytic activity assays and Western and Northern blotting. In the present study, we examined which features of the flavonoid structures were associated with induction of UGT1A1 and whether common drug-metabolizing enzyme inducers also produce this induction. We also determined whether flavonoid treatment affected sulfate conjugation and CYP1A1 activity. We used intact Hep G2 cells for these studies, with chrysin as the model substrate. Both glucuronidation and sulfation were measured. Hep G2 cells were pretreated for 3 days with 25 microM concentrations of 22 flavonoids (n = 4-12). Only four flavonoids demonstrated induction of glucuronidation similar to that of chrysin (i.e., 3-5-fold in the intact cells). These were acacetin, apigenin, luteolin, and diosmetin, all of which, like chrysin, are 5,7-dihydroxyflavones with varying substituents in the B-ring. 5-Hydroxy-7-methoxyflavone and 5-methyl-7-hydroxyflavone produced a modest 1.5 to 2-fold induction, whereas all other flavonoids examined were without effect. None of the flavonoids caused more than a modest change in sulfation activity (60-140% of control). In contrast, all tested 5,7-dihydroxyflavones and -flavonols induced CYP1A1 activity (ethoxyresorufin deethylation). Of seven common drug-metabolizing enzyme inducers only 3-methylcholanthrene and oltipraz showed modest induction of chrysin glucuronidation but not 2,3,7,8-tetrachlorodibenzo-p-dioxin or phenobarbital. Together, these results strongly suggest that the flavonoid induction of UGT1A1 is through a novel nonaryl hydrocarbon receptor-mediated mechanism.
PMID: 11950788
Piperine: This may be another pGp efflux pump inhibitor. (PMID: 16243320) It may alter gut permeability resulting in increased absorption of some drugs (PMID: 12046863). I don't consider either of these putative activities to be particularly relevant. However, it appears to be an inhibitor of glucuronidation, and this may well be useful. In rats, it inhibited glucuronidation of EGCG in the gut by 40%, but did nothing in liver cells. See below and also PMID: 8347144.
J Nutr. 2004 Aug;134(8):1948-52. Links
Piperine enhances the bioavailability of the tea polyphenol (-)-epigallocatechin-3-gallate in mice.Lambert JD, Hong J, Kim DH, Mishin VM, Yang CS.
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, State University of New Jersey, Piscataway, NJ 08854, USA. joshua_lambert@hotmail.com
(-)-Epigallocatechin-3-gallate (EGCG), from green tea (Camellia sinensis), has demonstrated chemopreventive activity in animal models of carcinogenesis. Previously, we reported the bioavailability of EGCG in rats (1.6%) and mice (26.5%). Here, we report that cotreatment with a second dietary component, piperine (from black pepper), enhanced the bioavailability of EGCG in mice. Intragastric coadministration of 163.8 micromol/kg EGCG and 70.2 micromol/kg piperine to male CF-1 mice increased the plasma C(max) and area under the curve (AUC) by 1.3-fold compared to mice treated with EGCG only. Piperine appeared to increase EGCG bioavailability by inhibiting glucuronidation and gastrointestinal transit. Piperine (100 micromol/L) inhibited EGCG glucuronidation in mouse small intestine (by 40%) but not in hepatic microsomes. Piperine (20 micromol/L) also inhibited production of EGCG-3"-glucuronide in human HT-29 colon adenocarcinoma cells. Small intestinal EGCG levels in CF-1 mice following treatment with EGCG alone had a C(max) = 37.50 +/- 22.50 nmol/g at 60 min that then decreased to 5.14 +/- 1.65 nmol/g at 90 min; however, cotreatment with piperine resulted in a C(max) = 31.60 +/- 15.08 nmol/g at 90 min, and levels were maintained above 20 nmol/g until 180 min. This resulted in a significant increase in the small intestine EGCG AUC (4621.80 +/- 1958.72 vs. 1686.50 +/- 757.07 (nmol/g.min)). EGCG appearance in the colon and the feces of piperine-cotreated mice was slower than in mice treated with EGCG alone. The present study demonstrates the modulation of the EGCG bioavailablity by a second dietary component and illustrates a mechanism for interactions between dietary chemicals.
PMID: 15284381
From my brief consideration of this, it looks like quercetin should help resveratrol bioavailability, perhaps a fair amount. Luteolin appears as though it should hurt more than help, and piperine looks like it might help some, but I'm not sure how much. What is needed here is for someone to give these compounds to human volunteers along with some resveratrol, stick a needle in their arm and quantitate things. I have a strong suspicion that that has not yet happened, unless maybe Sirtris did it, but they probably aren't talking. I'd like to hear more from AOR.