Phase I Dose Escalation Pharmacokinetic Study in Healthy Volunteers of Resveratrol, a Potential Cancer Chemopreventive Agent

David J. Boocock; Guy E.S. Faust; Ketan R. Patel; Anna M. Schinas; Victoria A. Brown; Murray P. Ducharme; Tristan D. Booth; James A. Crowell; Marjorie Perloff; Andreas J. Gescher; William P. Steward; Dean E. Brenner

doi:10.1158/1055-9965.EPI-07-0022

DOI: 10.1158/1055-9965.EPI-07-0022 Published June 2007

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Figure 1.
Structure of resveratrol.
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Figure 2.
Mean plasma concentrations of resveratrol (A), two resveratrol monoglucuronides (B and C), and resveratrol-3-sulfate (D) versus time in healthy volunteers who received a single dose of resveratrol at 0.5 (♦), 1 (□), 2.5 (▵), or 5 g (▪). Points, mean of 10 volunteers per dose level. Insets, coefficients of variation.
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Figure 3.
Relationship between dose of resveratrol and AUC_0-t (A) or C_max (B) for resveratrol (□), two resveratrol monoglucuronides (♦, ▴), and resveratrol-3-sulfate (▪) in healthy volunteers, who received a single dose of resveratrol at either 0.5, 1, 2.5, or 5 g. Points, mean of 10 volunteers per dose level; bars, SD.
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Figure 4.
Excretion of resveratrol (closed columns), two resveratrol monoglucuronides (open and dotted columns), and resveratrol-3-sulfate (striped columns) in the urine of healthy volunteers who received resveratrol. A. Cumulative excretion over 24 h after ingestion of resveratrol at 0.5, 1, 2.5, or 5 g. B. Rate of excretion (per hour) during five collection intervals within 24 h post-administration of 0.5 g resveratrol. Columns, mean of 10 individuals, expressed as percentage of dose; bars, SD.

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Table 1.

Adverse events in healthy volunteers after a single dose of resveratrol

Nature of event*	No. individuals
		Dose level (g)
		0.5	1.0	2.5	5.0
Unlikely to be drug related
Raised urea	1	0	1	0
Raised creatinine	1	0	0	0
Low total protein	1	0	0	0
Raised albumin	0	0	0	1
Raised phosphate	2	0	1	2
Low phosphate	0	1^†	0	0
Raised bilirubin	0	0	1	0
Raised calcium	1	0	0	0
Raised glucose	1	3	1	1
Low CO₂	0	0	2^‡	2
Raised lactate dehydrogenase	1	0	0	1
Low lactate dehydrogenase	0	0	0	1
Raised cholesterol	0	2	0	0
Low WBC count	0	0	1	0
Raised neutrophil count	0	1	0	0
Raised lymphocyte count	0	1	0	0
Raised eosinophil count	0	0	0	1
Low basophil count	0	0	1	0
Raised platelet count	1	1	0	0
Low hematocrit	2	0	0	0
Raised chloride	1	1	0	1
Cellulitic foot infection	0	1	0	0
Flatulence	0	1	0	0
Nausea	0	1	0	0
Loose stool	0	2	0	0
Panic attack	0	1	0	0
Headache	0	1	1	0
Possibly drug related
Raised bilirubin	0	2^‡	0	0
Raised alanine aminotransferase	0	1	0	0

↵* All (except where indicated) National Cancer Institute Common Toxicity Criteria grade 1.
↵† National Cancer Institute Common Toxicity Criteria grade 2.
↵‡ In one of these two individuals, event was National Cancer Institute Common Toxicity Criteria grade 2.

Table 2.

Pharmacokinetics of resveratrol and three metabolites in the plasma of volunteers after a single oral dose

Variable	Dose level (g)
Variable		0.5	1.0	2.5	5.0
Resveratrol
AUC_inf (ng h/mL)	223.7*	544.8 (57.2)	786.5 (36.2)	1,319 (59.1)
C_max (ng/mL)	72.6 (48.9)	117.0 (73.1)	268.0 (55.3)	538.8 (72.5)
T_max (h)	0.833 (0.5-1.5)	0.759 (0.5-4.0)	1.375 (0.5-4.0)	1.500 (0.67-5.0)
C_av (ng/mL)	8.36 (57.8)	18.04 (51.6)	32.25 (43.0)	51.90 (80.7)
Half-life (h)	2.85*	8.87 (91.1)	4.22 (51.6)	8.52 (95.8)
CL/F (L/h)	2,235*	2,593 (65.1)	3,471 (29.9)	4,930 (50.0)
CL_R (L/h)	1.177 (102.5)	0.696 (71.5)	0.656 (53.1)	1.443 (139.2)
V/F (liters)	9,198*	19,298 (54.3)	22,226 (67.3)	66,991 (112)
Glucuronide 1
AUC_inf (ng h/mL)	1,919 (33.6)	3,059 (60.9)	5,664 (27.7)	9,923 (40.9)
C_max (ng/mL)	404.6 (35.3)	473.6 (76.8)	874.4 (37.5)	1,285 (55.4)
T_max (h)	2.00 (1.0-6.0)	2.250 (1.0-6.0)	2.375 (1.0-8.0)	2.00 (1.5-5.0)
C_av (ng/mL)	76.9 (37.2)	110.3 (56.1)	215.5 (43.5)	344.1 (51.5)
Half-life (h)	2.85 (48.6)	7.27 (93.9)	10.6 (92.9)	7.90 (39.1)
CL/F (L/h)	282.7 (27.3)	493.5 (74.7)	469.5 (25.7)	590.6 (45.2)
Glucuronide 2
AUC_inf (ng h/mL)	1,287 (21.7)	2,589 (66.4)	4,320 (32.9)	8,546 (62.3)
C_max (ng/mL)	369.5 (39.6)	672.6 (81.1)	1,626 (71.5)	1,735 (66.4)
T_max (h)	1.500 (1.0-5.0)	1.750 (1.0-5.1)	2.000 (1.0-6.0)	2.520 (1.5-8.0)
C_av (ng/mL)	51.0 (27.6)	99.9 (66.2)	193.8 (39.3)	317.8 (65.6)
Half-life (h)	3.09 (69.8)	6.64 (92.1)	8.42 (88.9)	5.83 (51.2)
CL/F (L/h)	408.8 (26.7)	642.5 (83.0)	636.9 (32.6)	1,017 (94.6)
3-Sulfate
AUC_inf (ng h/mL)	4,049 (26.6)	10,053 (73.2)	16,984 (41.7)	30,898 (46.1)
C_max (ng/mL)	1,135 (25.7)	2,102 (81.3)	2,786 (27.2)	4,294 (48.0)
T_max (h)	1.500 (1.0-5.0)	2.000 (1.0-5.0)	2.000 (1.0-5.2)	2.050 (1.0-6.0)
C_av (ng/mL)	172.0 (23.2)	402.6 (70.5)	597.0 (27.0)	1,089 (49.4)
Half-life (h)	3.21 (56.6)	4.51 (82.8)	11.5 (95.5)	7.71 (42.3)
CL/F (L/h)	131.2 (25.8)	151.8 (62.7)	171.2 (40.0)	207.8 (63.9)

NOTE: Values are the mean of n = 10 with coefficient of variation (in percent) or range in brackets.
Abbreviations: AUC_inf, area under the concentration versus time curve to time infinity; C_max, maximal plasma concentration; T_max, median time of maximal plasma concentration; C_av, average plasma concentration; CL/F, apparent total body clearance (calculated as dose/AUC_inf); CL_R, apparent renal clearance approximated by amount excreted with urine within 24 h over AUC_0-24; V/F, apparent volume of distribution.
↵* n = 1, value for AUC_inf at the lowest dose could be established in only one participant.