Forty-two eligible participants initiated the study intervention. There were 11 men and 31 women. Average age was 40 years (range of 19 – 64 years) and average body mass index was 25.4 kg/m2 (range of 20.0 – 42.3 kg/m3). Safety data were analyzed on all 42 participants. CYP and Phase II enzyme activity were assessed in 40 participants because one participant withdrew participation after taking the first resveratrol dose and one participant was unavailable for the post-dosing enzyme activity assessment.
summarizes the CYP phenotypic indices determined before and after 4 weeks of resveratrol administration. For CYP1A2 activity, assessed by the metabolic ratio of caffeine and paraxanthine, data from four participants were not included in the analysis because of the presence of high caffeine and paraxanthine levels in the predosing samples. Similar to those reported previously (19
), there were large between-subject variations in CYP1A2 activity. The geometric mean baseline caffeine/paraxanthine ratio was 3.95 with values ranging from 1.31 to 21.4. After 4 weeks of daily resveratrol administration, the caffeine/paraxanthine ratio decreased significantly (p
= 0.0005), suggesting an induction of CYP1A2 activity. The geometric mean ratio of post- over pre-intervention CYP1A2 index was 0.84 (90% CI, 0.78–0.91), representing a geometric mean change of 16%.
CYP phenotypic indices before and after 4 weeks of daily resveratrol administration (1 gm QD).
For CYP3A4 activity, assessed by the AUC of buspirone, data from one participant was not obtained because the plasma buspirone concentrations of this individual were highly variable, not allowing for the AUC calculation. Large between-subject variations were also observed for CYP3A4 enzyme activity. The geometric mean baseline buspirone AUC was 73.2 [(ng/ml)·min] with values ranging from 7.9 to 1,322 [(ng/ml)·min]. Four weeks of resveratrol administration resulted in a statistically significant increase in buspirone AUC (p = 0.01), suggesting inhibition of CYP3A4 activity. The geometric mean ratio of post- over pre-intervention buspirone AUC was 1.33 (90% CI, 1.11 – 1.59), representing a geometric mean change of 33%.
For CYP2D6 activity, assessed by the metabolic ratio of dextromethorphan and dextrorphan, data for one participant was not available due to a missed collection. In addition, dextromethorphan levels were not detectable in one participant in the baseline sample and in four participants in the post-intervention sample. These data were not included in the analysis. The baseline geometric mean dextromethorphan/dextrorphan molar ratio was found to be 0.07 with values ranging from 0.002 to 7.96. Resveratrol intervention resulted in significantly increased post-intervention dextromethorphan/dextrorphan molar ratio (p = 0.01), suggesting inhibition of CYP2D6 activity. The geometric mean ratio of post- over pre-intervention CYP2D6 index was 1.70 (90% CI, 1.23 – 2.19), representing a geometric mean change of 70%.
For CYP2C9 activity, assessed by the metabolic ratio of losartan and E3174, data was unavailable for one participant due to a missed collection. The baseline geometric mean losartan/E3174 ratio was 1.02 with values ranging from 0.37 to 5.06. Four weeks of resveratrol intervention resulted in a significant increase in CYP2C9 phenotypic index (p < 0.0001). The geometric mean ratio of post- over pre-intervention CYP2C9 index was 2.71 (90% CI, 2.22–3.31), representing a geometric mean change of 171%.
We examined the change in CYP indices stratified by baseline level because univariate regression analysis showed that the change in CYP indices was dependent on baseline values. illustrates the geometric mean percent change in CYP indices by tertile based on the baseline level. CYP1A2 is induced in individuals with enzyme activity in the lowest and middle tertiles. Inhibition of CYP3A4 and 2D6 indices was statistically significant in individuals with enzyme activity in the highest tertile, whereas inhibition of CYP2C9 index was significant in all tertiles.
Percent change in CYP phenotypic indices by baseline activity tertile. a: p <0.05, b: p < 0.01, c: p < 0.005, d: p < 0.001.
summarizes the GST activity and GST-π level in peripheral blood lymphocytes before and after 4 weeks of daily resveratrol administration. Resveratrol intervention had minimal effects on overall GST activity (p = 0.77) and GST-π level (p = 0.10). summarizes the total and direct bilirubin determined before and after 4 weeks of daily resveratrol administration. Because bilirubin is primarily cleared from the body by the liver through conjugation reactions mediated by UGT1A1, individuals with high bilirubin levels tend to have low UGT1A1 activity and vice versa. Resveratrol intervention did not affect the overall serum bilirubin level (p = 0.90 for total bilirubin; p = 0.27 for direct bilirubin).
Blood lymphocyte GST enzyme activity and GST-π levels before and after 4 weeks of daily resveratrol administration (1 gm QD).
Serum total and direct bilirubin levels before and after 4 weeks of daily resveratrol administration (1 gm QD).
Similarly, we also examined the change in Phase II enzyme measurements stratified by baseline level because univariate regression analysis showed that the change in Phase II enzymes was dependent on baseline value. illustrates the change in Phase II enzyme measurements by tertile based on the baseline level. Individuals with low baseline GST-π showed a statistically significant increase with resveratrol intervention. Induction of UGT1A1 activity, assessed by serum total bilirubin level, was significant in those with low baseline activity.
Percent change in GST pi expression, total GST activity, and UGT1A1 activity, by baseline expression/activity level. UGT1A1 activity was assessed by serum total bilirubin levels. a: p < 0.005, b: p < 0.01.
summarizes the plasma resveratrol and metabolite concentrations 1 hr after a single oral dose of 1 gm of resveratrol. Previous studies have shown that plasma resveratrol concentrations reach maximum concentration approximately 1 hr after a single oral dose (27
). The mean 1 hr post dosing plasma resveratrol concentration was 72.7 ng/ml with concentration values ranging from 8.3 to 404.4 ng/ml. The 1 hr post dose plasma concentrations of resveratrol metabolites were much higher than those observed for the parent compound. The major resveratrol metabolites were identified by liquid chromatography-tandem mass spectrometry as described previously (24
), with one metabolite conjugated with a glucuronide and a sulfate moiety (glucuronide-sulfate), two metabolites with a glucuronide moiety (monoglucuronide 1 and monoglucuronide 2), one metabolite with two sulfate moieties (disulfate), and one metabolite with a sulfate moiety at the 3-hydroxyl position (3-sulfate). The mean plasma concentrations of glucuronide-sulfate, monoglucuronide 1, monoglucuronide 2, disulfate, and 3-sulfate metabolite were 339.6, 619.5, 767.9, 359.3, 2,376.6 ng/ml, respectively, significantly higher than that of the parent compound.
Plasma resveratrol and metabolite concentrations 1 hr post a single oral dose of 1 gm of resveratrol.
lists the reported adverse events deemed possibly or probably related to study agent because of temporal proximity. Four weeks of daily administration of pharmacological doses of resveratrol was well tolerated in healthy participants. All reported adverse events were CTC Grade 1 or 2, and many were very mild and transient. One participant withdrew from study participation after the first dose of resveratrol due to diarrhea. One post-menopausal woman (BMI 36.9 kg/m2) experienced new onset, persistent peri-menopausal symptoms (hot flashes, insomnia) which required a 50% dose reduction. Four weeks of resveratrol dosing did not result in any clinically significant changes in blood chemistry and hematology measurements (data not shown).
Summary of adverse events possibly or probably related to resveratrol.