Drug-food interactions are increasingly recognized as having potential clinical implications.2,3) Recent investigations have shown that several dietary ingredients modulate not only drug-metabolizing enzymes but also drug transporters in intestinal epithelial cells 3,4) which functionally express ATP-binding cassette transporters such as P-glycoprotein and multi-drug resistance associated proteins (MRPs).5,6) For example, piperine, a major constituent of black pepper, and capsaicin, a pungent component of chili pepper, have been shown to inhibit P-glycoprotein-mediated drug efflux. 7,8) Also, curcumin, a yellow pigment of turmeric, has been reported to modulate P-glycoprotein expression.9,10) Thus, modulation of both the function and expression of intestinal transporters by dietary ingredients may affect the uptake of their substrates.The current study was undertaken to investigate the effects of piperine, capsaicin and curcumin, daidzein (a soybean isoflavone), genistein (a soybean isoflavone), sesamin (a sesame lignan) and taurine (an amino acid in seafood) (Fig. 1) on the function and expression of P-glycoprotein. Pharmacokinetic and pharmacodynamic interactions involving these dietary ingredients, which are frequently consumed as dietary supplements or health foods, may occur in patients receiving drug therapy. In the present study, we used vinblastine-resistant colon carcinoma LS-180 cells (LS-180V cells), an intestinal model for the analysis of both transcriptional and functional changes of transporters such as P-glycoprotein. 11,12) February 2010 255 The present study was conducted to investigate the functional and transcriptional modulation of P-glycoprotein (MDR-1) by several dietary ingredients (piperine, capsaicin, daidzein, genistein, sesamin, curcumin, taurine) in vinblastine-resistant colon carcinoma LS-180 cells (LS-180V cells). The amount of rhodamine 123 accumulated in LS-180V cells was significantly increased by capsaicin, piperine and sesamin, whereas it was significantly reduced by daidzein and genistein which stimulated the efflux of rhodamine 123. These results suggest that the P-glycoprotein-mediated efflux is inhibited by piperine, capsaicin and sesamin and stimulated by daidzein and genistein. The concurrent addition of piperine and capsaicin seemed to inhibit synergistically the P-glycoproteinmediated efflux. Pretreatment with sesamin for 48 h caused a significant increase in MDR1 mRNA expression without a significant effect on the expression of P-glycoprotein or accumulation of rhodamine 123. Similar pretreatment with other ingredients had little effect on the expression of MDR1 mRNA or P-glycoprotein, suggesting that they do not cause transcriptional modulation of P-glycoprotein. Piperine, genistein and curcumin have been suggested to stimulate P-glycoprotein-mediated efflux without increasing P-glycoprotein expression. In LS-180V cells, significant increases in mRNA levels of multi-drug resistance associated protein 1 (MRP1) or MRP3 were observed on pretreatment with capsaicin, daid...

The present study was conducted to investigate the effects of repeated treatment with morphine on the drug's antinociceptive effects, intestinal absorption, and transepithelial transport. The antinociceptive effects of morphine in rats were markedly decreased after repeated oral administration of the drug for 5 d, indicating the development of tolerance. In the morphine-tolerant rats, intestinal absorption of morphine was determined using the in situ loop method. Absorption of morphine from the jejunum was significantly decreased after repeated administration. The permeability of human intestinal epithelial Caco-2 cells was increased in the efflux direction after repeated treatment. The repeated administration of morphine also reduced the cellular accumulation and efflux of P-glycoprotein substrates ([ 3 H]vincristine and rhodamine123) from Caco-2 cells, suggesting that it enhances P-glycoprotein-mediated efflux in Caco-2 cells. These results suggest that repeated use enhances the efflux of morphine in the epithelial cells of the small intestine, subsequently decreasing its intestinal absorption.