Clinical Characteristics and Pharmacokinetics of Purified Soy Isoflavones: Multiple-Dose Administration to Men with Prostate Neoplasia

Abstract

A phase I clinical trial was conducted to determine the safety, pharmacokinetic parameters, and efficacy of orally administered isoflavones (genistein and daidzein, potential cancer chemotherapeutic agents) over a 3-mo period in men with prostate neoplasia. Twenty men, ages 40 and above, with stage B, C, or D adenocarcinoma of the prostate were treated with a multiple-dose regimen of a soy isoflavone formulation (delivering approximately 300 or 600 mg/day genistein and half this much daidzein) for 84 days. The delivered dose of isoflavones was more than 10-fold higher than that typically taken by prostate cancer patients. In men with prostate cancer, relatively minor side effects of chronic isoflavone treatment were observed including some estrogenic effects (breast changes, increased frequency of hot flashes). Serum dehydroepiandrosterone was decreased by 31.7% (P = 0.0004) at the end of treatment. Except for those subjects whose prostate-specific antigen (PSA) values were below 0.4 ng/ml, subjects had a history of increasing PSA levels prior to the trial. This increase continued during the trial both while on soy isoflavones and after treatment was discontinued. On average the rate of rise accelerated after soy isoflavones were discontinued, but that difference did not attain statistical significance. Genistein and daidzein were rapidly cleared from plasma and excreted in urine. Pharmacokinetic data for chronic dose administration were similar to single-dose administration for the isoflavones investigated except that we observed slightly longer circulation time for daidzein.

Effects of soy phytoestrogens on the prostate

“…Soy was also not effective in reducing PSA levels in a phase I clinical trial to determine the safety of high-dose oral isoflavones in 20 men with prostate cancer. 31 Fischer et al 31 gave subjects with stage B, C or D prostate cancer a multiple-dose regimen of a soy isoflavone formulation (delivering approximately 300 or 600 mg/day genistein and half this much daidzein) for 84 days. Seven patients were excluded from the analysis of PSA values because the respective PSA was undetectable or o0.4 ng/ml.…”

Dietary Manipulation for Therapeutic Effect in Prostate Cancer

“…(Akiyama et al, 1987) c. (Sallman et al, 2007) d. (Dorai et al, (Bemis et al, 2004;Li & Sarkar, 2002;El Touny & Banerjee, 2007;Park et al, 2005) b. (Ivanov et al, 2007) c. (Aziz et al, 2006;Chen et al, 2010) d. (Yu et al, 2008; pharmacokinetic study (Fischer et al, 2004), though serum dehydroepiandrosterone was reduced by 31.7% (P = 0.0004) at the end of the study, and estrogenic side effects were encountered. Biologically relevant concentrations of genistein, commensurate with in vitro activity, can be achieved with high doses of genistein -enriched isoflavone extracts (Takimoto et al, 2003).…”

Dietary Phytochemicals as Cancer Preventive Agents: Efficacy and Mechanisms

“…Pharmacokinetic studies have shown that genistein has very long half-life (46 h) after oral administration and that different dose of genistein show no correlation of AUC, suggesting that there may be unknown mechanism of elimination and recycling system [135,136]. In human, genistein is extensively metabolized and the plasma level of unconjugated form is very low [137,138]. Several human clinical pharmacokinetic studies have revealed that the level of total genistein in plasma is within micro molar range while the genistein aglycone, a biological active form compared to genistein conjugates, is in hundred nano molar range [138,139].…”

“…In human, genistein is extensively metabolized and the plasma level of unconjugated form is very low [137,138]. Several human clinical pharmacokinetic studies have revealed that the level of total genistein in plasma is within micro molar range while the genistein aglycone, a biological active form compared to genistein conjugates, is in hundred nano molar range [138,139]. There were adverse events in a clinical trial using genistein 30 mg/day for 6 weeks, but all events, including gastrointestinal and cardiovascular, were mild and no patients aborted the protocol due to the events [134].…”