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Co‐administration of piperine and docetaxel results in improved anti‐tumor efficacy via inhibition of CYP3A4 activity
Author(s) -
Makhov Peter,
Golovine Konstantin,
Canter Daniel,
Kutikov Alexander,
Simhan Jay,
Corlew Melany M.,
Uzzo Robert G.,
Kolenko Vladimir M.
Publication year - 2011
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.21469
Subject(s) - docetaxel , piperine , pharmacology , pharmacokinetics , cyp3a4 , in vivo , medicine , prostate cancer , chemistry , chemotherapy , cancer , metabolism , biology , cytochrome p450 , microbiology and biotechnology
BACKGROUND Docetaxel is the mainline treatment approved by the FDA for castration‐resistant prostate cancer (CRPC) yet its administration only increases median survival by 2–4 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. © 2011 Wiley Periodicals, Inc.