Ginsenoside metabolites inhibit P-glycoprotein in vitro and in situ using three absorption models.
P-glycoprotein, an ATP-dependent transporter expressed in the gastrointestinal tract and tumor cells, mediates the efflux transport of multiple drugs. Inhibition or induction of P-glycoprotein by herbal ingredients can lead to herb-drug interactions and thus influence the activities of P-glycoprotein substrate drugs. The present study aimed to explore the effect of nine naturally occurring ginsenosides and their intestinal bacterial metabolites on P-glycoprotein-mediated transport. The results showed that three ginsenoside metabolites (CK, Ppd, and Ppt) formed by intestinal bacteria significantly enhanced rhodamine 123 retention in Caco-2 cells, increased the absorptive permeability of rhodamine 123, and decreased the efflux ratio of digoxin in two absorption models, which were comparable to the effects of the known P-glycoprotein inhibitor verapamil. However, the prototype ginsenosides such as Rb1, Rb2, and Re showed no inhibitory effect on P-glycoprotein activity. In situ intestinal perfusion experiments also showed that CK, Ppd, and Ppt increased the absorption rate constant and permeability coefficient of rhodamine 123. Long-term treatment with CK, Ppd, and Ppt had no effect on P-glycoprotein mRNA expression in Caco-2 cells. In conclusion, CK, Ppd, and Ppt are potent P-glycoprotein inhibitors, indicating an unpredictable herb-drug interaction when ginsenosides are coadministered orally with P-glycoprotein substrate drugs.
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
Na
N
Li
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
Dandan
D
Wang
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
Guangbo
G
Ge
Dalian Medical University, Dalian, China.
Xiuli
X
Wang
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
Yong
Y
Liu
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
Ling
L
Yang
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D018938:Caco-2 Cells; D004077:Digoxin / Q000378:metabolism*; D036145:Ginsenosides / Q000494:pharmacology*; D041743:Herb-Drug Interactions; D006801:Humans; D007408:Intestinal Absorption; D007422:Intestines / Q000382:microbiology; D008297:Male; D005894:Panax / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020112:Rhodamine 123 / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D036145:Ginsenosides; D020112:Rhodamine 123; D004077:Digoxin