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Makhov P , Golovine K , Canter D , Kutikov A , Simhan J , Corlew MM , Uzzo RG , Kolenko VM
Co-administration of piperine and docetaxel results in improved anti-tumor efficacy via inhibition of CYP3A4 activity
Prostate. 2012 May;72(6) :661-667
PMID: WOS:000301712500009    PMCID: PMC3208085   
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Abstract
BACKGROUND Docetaxel is the mainline treatment approved by the FDA for castration-resistant prostate cancer (CRPC) yet its administration only increases median survival by 24 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 pharmacokinetic activity 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. RESULTS. Inhibition of hepatic CYP3A4 activity resulted in an increased area under the curve, 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. In our studies, dietary consumption of piperine increases the therapeutic efficacy of docetaxel in a xenograft model without inducing more adverse effects on the treated mice. Prostate 72:661-667, 2012. (C) 2011 Wiley Periodicals, Inc.
Notes
Makhov, Peter Golovine, Konstantin Canter, Daniel Kutikov, Alexander Simhan, Jay Corlew, Melany M. Uzzo, Robert G. Kolenko, Vladimir M. National Institutes of Health[RO1 CA134463, P30 CA006927]; American Institute for Cancer[09A023]; Department of Defense[W81XWH-10-1-0187 (PC094474)]; CCSG Grant sponsor: National Institutes of Health Grants; Grant numbers: RO1 CA134463; CCSG; P30 CA006927; Grant sponsor: American Institute for Cancer Research Grant; Grant number: 09A023; Grant sponsor: Department of Defense Physician Research Training Award; Grant number: W81XWH-10-1-0187 (PC094474). 26 Wiley-blackwell Malden 911jg