title: Enhancement of paclitaxel transport and cytotoxicity by 7,3',4'-trimethoxyflavone, a P-glycoprotein inhibitor.
abstract: OBJECTIVE
  Paclitaxel has problems with respect to bioavailability and resistance. The aim of this study was to select a P-glycoprotein (Pgp)- inhibitory flavonoid to enhance paclitaxel bioavailability in the Caco-2 cell monolayer.
  
  
  METHODS
  Cytotoxicity and chemosensitization were determined using MTT assay. Paclitaxel transport was examined in the Caco-2 cell monolayer, which mimics the intestinal barrier. Paclitaxel concentrations were quantitated by HPLC assay using the internal standard method.
  
  
  RESULTS
  Chemosensitizing indeces of 7,3',4'-trimethoxyflavone (TMF) and verapamil was > 333 and 152, respectively. The basolateral (BL)- to-apical (AP) transport of paclitaxel was more than 10-fold greater than its AP-to-BL transport. TMF and verapamil increased the AP-to-BL transport of paclitaxel but decreased its BL-to-AP transport in a concentration-dependent manner. The net absorptive effect of 50 microM TMF on paclitaxel transport was comparable to that of 50 muM verapamil. In addition, AP loading of TMF increased the paclitaxel sensitivity of paclitaxel-resistant SK-MES-1/PT4000 cells overexpressing Pgp on the BL side.
  
  
  CONCLUSIONS
  These results indicate that TMF with low toxicity can be used as an enhancer of oral paclitaxel bioavailability and as a Pgp inhibitor.
authors.affiliation: Research Center for Resistant Cells and Department of Pharmacology, Chosun University Medical School, and BK21Team for Bio Hydrogen Production, Chosun University, Gwangju, South Korea.
authors.forename: Ju-Mi
authors.initials: JM
authors.lastname: Jeong
authors.forename: Cheol-Hee
authors.initials: CH
authors.lastname: Choi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003603:Cytotoxins / Q000493:pharmacokinetics* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D007529:Isoflavones / Q000493:pharmacokinetics* / Q000633:toxicity; D017239:Paclitaxel / Q000493:pharmacokinetics* / Q000633:toxicity; D012210:Rhamnose / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: C501827:7,3',4'-trihydroxy-5-O-alpha-L-rhamnopyranosylisoflavone; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003603:Cytotoxins; D007529:Isoflavones; D017239:Paclitaxel; D012210:Rhamnose