Enhancement of paclitaxel transport and cytotoxicity by 7,3',4'-trimethoxyflavone, a P-glycoprotein inhibitor.
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.
Jeong
Ju-Mi
JM
Research Center for Resistant Cells and Department of Pharmacology, Chosun University Medical School, and BK21Team for Bio Hydrogen Production, Chosun University, Gwangju, South Korea.
Choi
Cheol-Hee
CH
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
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