title: Co-administration of piperine and docetaxel results in improved anti-tumor efficacy via inhibition of CYP3A4 activity.
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 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.
authors.affiliation: Department of Urologic Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Makhov
authors.forename: Konstantin
authors.initials: K
authors.lastname: Golovine
authors.forename: Daniel
authors.initials: D
authors.lastname: Canter
authors.forename: Alexander
authors.initials: A
authors.lastname: Kutikov
authors.forename: Jay
authors.initials: J
authors.lastname: Simhan
authors.forename: Melany M
authors.initials: MM
authors.lastname: Corlew
authors.forename: Robert G
authors.initials: RG
authors.lastname: Uzzo
authors.forename: Vladimir M
authors.initials: VM
authors.lastname: Kolenko
mesh_terms: D000470:Alkaloids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D052117:Benzodioxoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D000077143:Docetaxel; D004347:Drug Interactions; D008297:Male; D051379:Mice; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D053284:Polyunsaturated Alkamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000470:Alkaloids; D052117:Benzodioxoles; D065692:Cytochrome P-450 CYP3A Inhibitors; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D043823:Taxoids; D000077143:Docetaxel; D051544:Cytochrome P-450 CYP3A; C008922:piperine