**4.1 Pharmacology**

Resveratrol is well-absorbed, but has poor bioavailability due to extensive first pass metabolism by the liver.

A pharmacokinetic study of trans-resveratrol (25, 50, 100 or 150mg single doses, repeated over 13 dosings) showed Cmax detected 48 to 90 minutes post-dosing (Almeida et al., 2009), but there was wide interindividual variability reported, also noted in another pharmacokinetic study (Nunes et al., 2009). In another study in 40 healthy volunteers given a single dose ten times the quantities used in the previous study (500, 1000, 2,500 or 5,000mg), peak plasma concentrations were achieved in 90 minutes, and were associated with a range of plasma resveratrol concentrations between 73 and 539 ng/mL (Boocock et al., 2007). Absorption may be faster after oral dosing (Goldberg et al., 2003), possibly due to delayed absorption by food (Vaz-da-Silva et al., 2008).

Resveratrol is rapidly metabolized. Radioactively labeled carbon-14 distribution studies (Vitrac et al., 2003) have been performed in mice with trans-resveratrol; it distributes to the stomach, intestines, liver and kidney, regions of highest uptakes. Mice, like men (de Santi et al., 2000 a,b,c) also form both sulfur and glucuronide conjugates, but a proportion remains unchanged as trans-resveratrol. A toxicological study with trans-resveratrol (as resVida®) in rats over 4 weeks has tested up to 300 mg/kg/d, with no observed serious adverse events (Edwards et al., 2011).

A phase I trial and repeated dose study to determine safety, pharmacokinetics and the effect on insulin-like growth factor (IGF) axis by resveratrol was recently reported (Brown et al., 2010). Doses of 0.5, 2.5 or 5.0 g per day over 29 days was given to forty volunteers. Levels of resveratrol metabolites in plasma were about 20 times higher than that of free resveratrol, and a reduction of circulating plasma IGF-1 and IGFBP-3 was noted (P< 0.04 in both). It is not clear to what extent the metabolites contributed to the fall in plasma IGF-1 and IGFBP-3 levels.

Dietary Manipulation for Therapeutic Effect in Prostate Cancer 297

Reduced cholesterol but no

Mean elimination half – lives of genistein was 3.2h and daidzein

Apoptosis in treated patient specimens significantly higher than controls. No changes in

Reduction of rate of rise of PSA in whole group. Serum genistein concentrations increased from 0.11 to 0.65µM and daidzein from 0.11 to 0.51µM. PSA stabilization in 83% of hormone sensitive group and 35% hormone insensitive

Cmax between 4.3 and 16.3µM, half – life between 15 and 22h.


One patient had PSA decline >50% and 8 patients had PSA

Reduction of testosterone in 61% of treatment group vs 33% of controls. PSA stabilization in 69% of treatment group vs 55%

Statistically significant reduction in slope of PSA induced by treatment. Increase in PSA doubling time from 445 to 1150 days (2.6 fold) with

PSA, testosterone.

(Urban et al., 2001)

(Busby et al., 2002)

(Jarred, 2002)

(Hussain et al.,

(Takimoto et al.,

(Fischer et al., 2004)

(Dalais et al., 2004)

(de Vere White et al., 2004)

(Kumar et al., 2004)

(Schroder et al.,

2005)

2003)

2003)

change in PSA

was 4.2h

patients

activity.

controls.

supplement

decline <50%.

31% reduction in dehydroepiandrosterone. Possibly slowing of PSA rise

(non – significant)

Intervention / Diet Design Outcome Reference

N=34. Randomized crossover trial. 6 week

Pharmacokinetic study

N=38, pilot study of treatment prior to prostatectomy. 18 treated vs 18 untreated patients. Non – randomized and non –

N=41, Pilot study in 3 groups (watchful waiting, rising PSA after local therapy, hormone

N=13. Phase I dose escalation with genistein

N=20. Phase I multiple dose, orally over 84 days

N=29, Pilot study. randomized comparison prior to prostatectomy

N=62, range of rising PSA states including post – prostatectomy, off

intermittent hormones,

N=59 evaluable patients who completed 12 weeks treatment. Gleason grade 6 or less.

N=46 (intent to treat). Randomized, double blind, crossover analysis. 10 week treatment periods separated by 4 week

cycle during

surveillance.

washout

at 2, 4, 8mg/kg.

intervention

blinded study

insensitive)

**Isoflavones** 

glycitein

Soy isoflavone preparation for 3 – 6

Single doses of two soy isoflavone preparations

Approximately 300mg or 600mg genistein and daidzein in soy formulation

Soy vs Soy + linseed vs wheat in bread diet

Genistein – rich extract

60mg soy isoflavone preparation

Supplement of soy, isoflavones, lycopene, silymarin, antioxidants

for 6 months

months

Single dose formulations of genistein, daidzein,

160mg daily of red clover isoflavone preparation (genistein, daidzein, formonetin, biochanin A)
