Pharmacokinetic profiles of resveratrol and pterostilbene were compared in male rats following a single intravenous dose, a single oral (gavage) dose, and daily oral (gavage) doses administered over 14 consecutive days. Following administration at equimolar doses, systemic exposure to pterostilbene was substantially greater than was systemic exposure to resveratrol: pterostilbene demonstrated markedly higher Cmax and AUC0–inf values, and its oral bioavailability was several-fold greater than the oral bio-availability of resveratrol.

Following intravenous dosing, total body clearance of resveratrol (11 L/h/kg) exceeded that of pterostilbene (2.7 L/h/kg). Clearance of resveratrol exceeded the rate of hepatic blood flow, while clearance of pterostilbene approached that value (4 L/h/kg). Pterostilbene exhibited a Vss value (5.3 L/kg) that was greater than total body water (~0.7 L/kg), suggesting extensive tissue distribution. Insufficient concentration–time data were available to fully characterize the T1/2 and Vss for resveratrol following intravenous dosing. However, unchanged resveratrol has been shown to be retained in tissues and to be the main form retained [1]. Higher clearance could account at least partially for the lower plasma levels and exposure (AUC0–inf) to resveratrol in comparison with pterostilbene.

Low plasma and tissue levels of resveratrol have been reported following oral administration to both experimental animals and humans [6, 41, 44]; reported in vivo plasma levels are significantly lower than are the concentrations of resveratrol that have commonly been used in static, metabolism-, and elimination-free in vitro systems [4, 6]. Plasma concentrations of Phase II metabolites of both resveratrol and pterostilbene are much higher than are the concentrations of the respective parent compounds. It has been proposed that these conjugates could serve as storage pools for the parent drugs, as has been demonstrated for estrone sulfate [40, 41]. The reported enterohepatic recirculation of resveratrol is generally consistent with this hypothesis [25]. An important open question, however, is whether these conjugates have any significant biological activity on their own; one recent publication has presented data demonstrating the in vitro biological activity of resveratrol sulfate metabolites [9, 16].

Comparisons of pharmacokinetic parameters after a single oral dose and 14 consecutive daily oral doses provided no clear evidence for autoinduction, autoinhibition, or saturation-limited elimination of either resveratrol or pterostilbene under the experimental conditions used. However, a trend of increasing F% with increasing dose was observed in animals exposed to pterostilbene.

While the present study was in progress, a report appeared describing the pharmacokinetics of pterostilbene [23] and comparing it to that of resveratrol in a different publication [12]. Reported clearance values following intravenous dosing with pterostilbene (5 mg/kg) or resveratrol (10 mg/kg) were 2.2 and 20.0 L/h/kg. These values compare to our CL values of 2.7 and 11.0 L/h/kg following intravenous administration of pterostilbene (11.2 mg/kg) and resveratrol (10 mg/kg). The F% values reported in those studies after oral (gavage) dosing with pterostilbene (10 mg/kg) or resveratrol (50 mg/kg) were 12.5 and 38.8%, respectively. These values contrast to our results of 66.9 and 29.8% for F% following administration of pterostilbene at 56 mg/kg or resveratrol at 50 mg/kg, respectively. While intravenous CL values were not dissimilar between the studies, the published results for F% of pterostilbene were surprising in two respects. First, the data from the two published reports suggest that the bioavailability of pterostilbene is lower than that of resveratrol, which is unexpected. Secondly, their reported bioavailability of pterostilbene is considerably lower than was found in our study. This could be explained if the doses used in our study had resulted in plasma drug concentrations in the saturating range. This is possible in view of our data where there was a trend of increasing F% value with increasing (tripling) dose. However, it is not possible to draw any definite conclusions on this matter, as the previously reported data involved different drug doses and were based on comparisons of nonequimolar drug administration protocols. In the present study, doses of resveratrol and pterostilbene were equimolar and were selected to allow adequate sensitivity over the sampling time for poorly bioavailable resveratrol. In addition, we have also systematically examined metabolic profiles, as agent metabolism appears to be the single most important factor impacting the bioavailability of polyphenols.

After careful examination, resveratrol was not detectable following dosing with pterostilbene. Therefore, pterostilbene does not appear to act as a prodrug for resveratrol. Phase II metabolites (sulfate and glucuronide conjugates) were the major metabolites of both drugs and were present in the plasma at levels that were substantially greater than levels of the parent compounds. The gastrointestinal tract, liver, and kidneys possess high levels of Phase II metabolizing activities [14, 39]; resveratrol has been reported to undergo rapid and extensive glucuronidation and sulfation, and the gastrointestinal tract may be the major site for its metabolism [13, 19].

In general, the values for sulfate AUC0–inf were substantially greater than the corresponding values for the glucuronide. At both dose levels, the AUC0–inf for pterostilbene sulfate was several orders of magnitude greater than the AUC0–inf for either pterostilbene glucuronide or pterostilbene itself. Differences for resveratrol were smaller: the AUC0–inf for resveratrol sulfate was from 9- to 24-fold higher than the AUC0–inf for resveratrol itself, but was only 2- to 4-fold greater than levels of resveratrol glucuronide following high dose exposure, and comparable to levels of resveratrol glucuronide (1.0–and 1.1-fold) at the low dose of resveratrol. Conversely, the AUC0–inf for pterostilbene glucuronide was much lower than the AUC0–inf for both the parent drug and its sulfate.

A dose-dependent decrease in resveratrol glucuronide/resveratrol with concomitant increases in resveratrol sulfate/resveratrol and its sulfate/glucuronide AUC0–inf ratios suggest a metabolic shift from glucuronidation to sulfation of resveratrol, possibly due to the saturation of the glucuronide pathway and/or differences in the respective values for their Km and Vmax values. A recent study in rats suggested that the specific conjugation pathway of resveratrol may be dose-dependent, with glucuronidation being the first step followed by sulfation, which may occur only after a certain level of resveratrol is reached [43]. On the other hand, a decrease in the sulfate/parent AUC0–inf ratio with dose may suggest saturation of the pterostilbene sulfation pathway under these conditions. Possible contributions of drug transporters to the pharmacokinetic profiles of resveratrol and pterostilbene cannot be discounted as has been proposed for resveratrol [40].

In summary, different exposure profiles of resveratrol, pterostilbene, and their glucuronide and sulfate conjugates are evident in the results of this study. Pterostilbene plasma levels and exposures were much higher than those of equimolar doses of resveratrol, regardless of dose or route of administration. Exposure to pterostilbene and pterostilbene sulfate was markedly greater than to resveratrol and its sulfate metabolite. On the other hand, exposure to resveratrol glucuronide was greater than to pterostilbene glucuronide. These differences stem from differences in absorption and metabolism of these two drugs.

In consideration of the apparent pharmacokinetic advantages of pterostilbene, studies to compare the efficacy and toxicity of pterostilbene and resveratrol are warranted to determine whether its improved pharmacokinetics translate into greater cancer chemopreventive and other pharmacologic activities.

These studies were supported by contract number N01-CN-43304 from the National Cancer Institute, Department of Health and Human Services. The authors thank Leigh Ann Senoussi for assistance in preparing the manuscript.

EDTA Ethylenediaminetetraacetic acid

QC Quality control

MP Mobile phase

LLOQ Lowest limit of quantitation

T_max Time to maximum plasma concentration

C_max Peak plasma concentration

AUCArea under the curve

t½ Elimination half-life

CL Clearance

Vss Apparent volume of distribution

F% Percent bioavailability