Phase I Pharmacokinetic and Pharmacodynamic Analysis of Unconjugated Soy Isoflavones Administered to Individuals with Cancer

Chris H. Takimoto, Kira Glover, Xiaoke Huang, Steven A. Hayes, Lilia Gallot, Mary Quinn, Borko D. Jovanovic, Alla Shapiro, Leticia Hernandez, Andrew Goetz, Victor Llorens, Ronald Lieberman, James A. Crowell, Brett A. Poisson, Raymond C. Bergan

Research output: Contribution to journalArticle

108 Scopus citations

Abstract

Preclinical studies suggest that the isoflavone genistein may have prostate cancer chemopreventive activity. Genistein has been shown to alter cellular levels of protein-tyrosine phosphorylation and is present at high levels in soy. This study was designed to measure the pharmacokinetic parameters of two different preparations of unconjugated soy isoflavones, PTI G-2535 and PTI G-4660 (which contain 43% and 90% genistein, respectively), in human subjects with cancer, to evaluate toxicity and obtain pilot data on in vivo effects on protein-tyrosine phosphorylation. Cohorts of four patients were given single doses of each preparation; each dose was separated by 1 week. Sequential cohorts received genistein at 2, 4, or 8 mg/kg orally. Pharmacokinetic sampling was performed after each dose, and tyrosine phosphorylation was measured in proteins extracted from peripheral blood mononuclear cells. One of 13 patients treated developed a treatment-related rash. No other toxicities were observed. Maximal plasma concentrations (C max) ranged between 4.3 and 16.3 μM for total genistein and 0.066 and 0.17 μM for free genistein. For PTI G-2535 and PTI G-4660, half-life was 15.03 and 22.41 h, respectively, and volume of distribution was 189.9 and 653.8 liters, respectively, and there was a trend toward higher area under the concentration curve for PTI G-2535 (P = 0.07 at the 8 mg/kg dose). Treatment-related increases in tyrosine phosphorylation were observed in peripheral blood mononuclear cells. Oral administration of soy isoflavones gives plasma concentrations of genistein that have been associated with antimetastatic activity in vitro.

Original languageEnglish (US)
Pages (from-to)1213-1221
Number of pages9
JournalCancer Epidemiology Biomarkers and Prevention
Volume12
Issue number11 II
StatePublished - Nov 1 2003

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

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    Takimoto, C. H., Glover, K., Huang, X., Hayes, S. A., Gallot, L., Quinn, M., Jovanovic, B. D., Shapiro, A., Hernandez, L., Goetz, A., Llorens, V., Lieberman, R., Crowell, J. A., Poisson, B. A., & Bergan, R. C. (2003). Phase I Pharmacokinetic and Pharmacodynamic Analysis of Unconjugated Soy Isoflavones Administered to Individuals with Cancer. Cancer Epidemiology Biomarkers and Prevention, 12(11 II), 1213-1221.