Abstract
Continuous use of St. John's wort decreases the bioavailabilities of a variety of drugs. This interaction is attributed to the induction of cytochrome P450 3A4 and/or P-glycoprotein. In this study, we aimed to examine the chronic effects of St. John's wort and its constituents, hyperforin and hypericin, on the expression and function of P-glycoprotein in an intestinal cell line, LS 180. We also examined the acute inhibitory effect of St. John's wort on P-glycoprotein by using LLC-GA5-COL150 cells, which overexpress P-glycoprotein. St. John's wort and hyperforin but not hypericin increased the expression of P-glycoprotein in LS 180 cells. Removal of St. John's wort resulted in a restoration of P-glycoprotein level within 48 h. The content of hyperforin in St. John's wort extract was high enough to induce P-glycoprotein, suggesting that the induction of P-glycoprotein by St. John's wort can be almost attributable to hyperforin. The LS 180 cells chronically exposed to St. John's wort or hyperforin exhibited the increase in the function of P-glycoprotein assessed by the efflux of digoxin, and the activities correlated well with P-glycoprotein level. On the other hand, St. John's wort and its two constituents did not show any acute effect on P-glycoprotein-mediated transport of digoxin. St. John's wort induced P-glycoprotein in vitro that functions as a drug efflux pump. Hyperforin is considered to be a primary cause of the inductive effect of St. John's wort. Long-term administration of St. John's wort may cause clinically significant decrease in the plasma concentrations of P-glycoprotein substrates.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.104.002485.
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ABBREVIATIONS: AUC, area under the concentration curve; TLC, thin-layer chromatography; WST-1, 2-(4-lodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt; Cmax, maximum plasma concentration; OATP8, organic anion-transporting polypeptide 8.
- Received September 28, 2004.
- Accepted January 5, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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