973 CO-ADMINISTRATION OF PIPERINE AND DOCETAXEL RESULTS IN IMPROVED ANTI-TUMOR EFFICACY VIA INHIBITION OF CYP3A4 ACTIVITY (2012)

You have accessJournal of UrologyProstate Cancer: Basic Research V1 Apr 2012973 CO-ADMINISTRATION OF PIPERINE AND DOCETAXEL RESULTS IN IMPROVED ANTI-TUMOR EFFICACY VIA INHIBITION OF CYP3A4 ACTIVITY Ervin Teper, Peter Makhov, Konstantin Golovine, Daniel Canter, Jay Simhan, Melany Corlew, Alexander Kutikov, Robert G. Uzzo, and Vladimir Kolenko Ervin TeperErvin Teper Huntingdon Valley, PA More articles by this author , Peter MakhovPeter Makhov Philadelphia, PA More articles by this author , Konstantin GolovineKonstantin Golovine Philadelphia, PA More articles by this author , Daniel CanterDaniel Canter Atlanta, GA More articles by this author , Jay SimhanJay Simhan Philadelphia, PA More articles by this author , Melany CorlewMelany Corlew Watertown, MA More articles by this author , Alexander KutikovAlexander Kutikov Philadelphia, PA More articles by this author , Robert G. UzzoRobert G. Uzzo Philadelphia, PA More articles by this author , and Vladimir KolenkoVladimir Kolenko Philadelphia, PA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1072AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Docetaxel is the mainline treatment approved by the FDA for castration-resistant prostate cancer (CRPC), yet its administration only increases median survival by two to four months. Docetaxel is metabolized in the liver by hepatic CYP3A4 activity. Piperine, a major plant alkaloid/amide, has been shown to inhibit the CYP3A4 enzymatic activity in a cell-free system. Thus, we investigated whether the co-administration of piperine and docetaxel could increase docetaxel's therapeutic index in vitro and in vivo. METHODS Liver CYP3A4 enzymatic activity was measured by fluorescence. In vivo docetaxel pharmacokinetic activity was analyzed by liquid chromatography. An in vivo xenograft model of human CRPC was utilized to assess the anti-tumor effect of docetaxel when co-administered with piperine. Statistical analysis was performed using a two-sided Student t test. Results are expressed as the mean ± SEM. Non-compartmental pharmacokinetic analysis was performed using WinNonlin. RESULTS Co-administration of piperine and docetaxel resulted in the most significant inhibition of tumor growth (188% vs. 461%, P=0.003) among the experimental groups. Importantly, the resulting increase in the mean plasma concentrations of docetaxel in mice fed piperine did not translate into an observed increase in toxicity during treatment. Inhibition of hepatic CYP3A4 activity resulted in an increased area under the curve (AUC), half-life and maximum plasma concentration of docetaxel when compared to docetaxel alone administration. The synergistic administration of piperine and docetaxel significantly improved the anti-tumor efficacy of docetaxel in a xenograft model of human CRPC. CONCLUSIONS Docetaxel is one of the most widely used cytotoxic chemotherapeutic agents and is currently the mainstay treatment for metastatic CRPC. Dietary constituents are important agents modifying drug metabolism and transport. Our work indicates that dietary consumption of piperine, an alkaloid/amide abundant in black pepper, increases the therapeutic efficacy of docetaxel in a xenograft mouse model without inducing notable adverse effects. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e396 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ervin Teper Huntingdon Valley, PA More articles by this author Peter Makhov Philadelphia, PA More articles by this author Konstantin Golovine Philadelphia, PA More articles by this author Daniel Canter Atlanta, GA More articles by this author Jay Simhan Philadelphia, PA More articles by this author Melany Corlew Watertown, MA More articles by this author Alexander Kutikov Philadelphia, PA More articles by this author Robert G. Uzzo Philadelphia, PA More articles by this author Vladimir Kolenko Philadelphia, PA More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...