title: 20(S)-ginsenoside Rh2 noncompetitively inhibits P-glycoprotein in vitro and in vivo: a case for herb-drug interactions.
abstract: P-glycoprotein (P-gp) is an ATP-dependent efflux transporter highly expressed in gastrointestinal tract and multidrug resistance tumor cells. Inhibition or induction of P-gp can cause drug-drug interactions and thus influence the effects of P-gp substrate drugs. Previous studies indicated that 20(S)-ginsenoside Rh2 [20(S)-Rh2] could synergistically enhance the anticancer effects of conventional chemotherapeutic agents at a nontoxic dose. The aim of present study was to investigate in vitro and in vivo whether 20(S)-Rh2 was a P-gp inhibitor and analyze the possible inhibitory mechanisms and potential herb-drug interactions. Results showed that in vitro, 20(S)-Rh2 significantly enhanced rhodamine 123 retention in cells and decreased the efflux ratio of digoxin, fexofenadine, and etoposide, which were comparable to the effects of the established P-gp inhibitor verapamil. However, the transport of 20(S)-Rh2 suggested that 20(S)-Rh2 was not a P-gp substrate. Furthermore, the inhibitory effect persisted for at least 3 h after removal of 20(S)-Rh2. Unlike P-gp substrates, 20(S)-Rh2 inhibited both basal and verapamil-stimulated P-gp ATPase activities. It also significantly decreased UIC2 binding fluorescence, a marker for conformational change of P-gp. In situ and in vivo experiments showed that 20(S)-Rh2 increased the area under the plasma concentration-time curve and maximum plasma concentration of digoxin, fexofenadine, and etoposide significantly without affecting terminal elimination half-time. Long-term treatment with 20(S)-Rh2 failed to affect intestinal P-gp expression in vitro and in vivo. In conclusion, 20(S)-Rh2 is a potent noncompetitive P-gp inhibitor, which indicates a potential herb-drug interaction when 20(S)-Rh2 is coadministered with P-gp substrate drugs. It could increase the absorption of P-gp substrate drugs without long-term induction of P-gp expression in rats.
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, Jiangsu, 210009, People's Republic of China.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Zhang
authors.forename: Fang
authors.initials: F
authors.lastname: Zhou
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Wu
authors.forename: Yi
authors.initials: Y
authors.lastname: Gu
authors.forename: Hua
authors.initials: H
authors.lastname: Ai
authors.forename: Yuanting
authors.initials: Y
authors.lastname: Zheng
authors.forename: Yannan
authors.initials: Y
authors.lastname: Li
authors.forename: Xiaoxuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Gang
authors.initials: G
authors.lastname: Hao
authors.forename: Jianguo
authors.initials: J
authors.lastname: Sun
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D018938:Caco-2 Cells; D004077:Digoxin / Q000493:pharmacokinetics; D005047:Etoposide / Q000493:pharmacokinetics; D036145:Ginsenosides / Q000494:pharmacology*; D041743:Herb-Drug Interactions; D006801:Humans; D007082:Ileum / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D016593:Terfenadine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D036145:Ginsenosides; D020112:Rhodamine 123; D005047:Etoposide; D004077:Digoxin; C055305:ginsenoside Rh2; D016593:Terfenadine; D014700:Verapamil; C093230:fexofenadine