Intestinal absorption mechanisms of ginsenoside Rh2: stereoselectivity and involvement of ABC transporters.
This study investigated the absorption mechanism of ginsenoside Rh2 to clarify the reasons for its poor absorption. Transepithelial transport across Caco-2 cell monolayers, cellular uptake, and in situ rat intestinal perfusion were examined. Cellular uptake of Rh2 was linear from 1 to 50 μM at 4°C, whereas it was saturated when the concentration exceeded 10 μM at 37°C. At 37°C, the uptake at 10 μM was linear in 60 min. Intracellular exposure in 240 min was 2173.70 and 979.38 ng·min/μg for S and R isomers, respectively. Transepithelial permeability of Rh2 was about 10⁻⁸ to 10⁻⁷ cm/s. Efflux ratios were above 1.5. Sodium dodecyl sulfate, sodium citrate, and sodium deoxycholate had no effect on Rh2 permeability. After intestinal perfusion for 3 h, 9.1% of 20(R)-Rh2 and 15.7% of 20(S)-Rh2 were absorbed. Cyclosporine, quercetin, and probenecid could improve the cellular uptake, absorptive permeability, and intestinal absorption. Carrier-mediated transport was the major absorption mechanism. Rh2 was a substrate of ABC transporters. The ABC-transporter-mediated efflux and the poor permeability were the major reasons for Rh2 poor absorption. The stereoselective absorption was significant. R isomer exhibited lower absorption profiles in all the experiments, possibly due to more potent efflux.
Gu
Y
Y
Key Laboratory of Drug Metabolism &amp; Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Wang
G-J
GJ
Wu
X-L
XL
Zheng
Y-T
YT
Zhang
J-W
JW
Ai
H
H
Sun
J-G
JG
Jia
Y-W
YW
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D004355:Drug Stability; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D036145:Ginsenosides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007408:Intestinal Absorption / Q000187:drug effects; D010477:Perfusion; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013696:Temperature; D013997:Time Factors
D018528:ATP-Binding Cassette Transporters; D036145:Ginsenosides; C055305:ginsenoside Rh2