title: Enhancement of oral bioavailability of 20(S)-ginsenoside Rh2 through improved understanding of its absorption and efflux mechanisms.
abstract: The development of 20(S)-ginsenoside Rh2 (Rh2s) as a chemoprevention agent is limited by its low oral bioavailability. The goals of this study were to determine the mechanisms responsible for its poor oral absorption and to improve its bioavailability by overcoming the barrier to its absorption. Comprehensive studies were conducted using the following models: 1) monolayers of Caco-2, parental, and multidrug resistance gene (MDR1)-overexpressing Madin-Darby canine kidney II (MDCKII) cells; 2) pharmacokinetics in wild-type (WT) FVB, MDR1a/b knockout [MDR1a/b⁻/⁻] FVB, and A/J mice; and 3) intestinal perfusion in WT, MDR1a/b⁻/⁻ FVB, and A/J mice. Two P-glycoprotein (P-gp) inhibitors, verapamil and cyclosporine A, substantially decreased the efflux ratio of Rh2s from 28.5 to 1.0 and 1.2, respectively, in Caco-2 cells. The intracellular concentrations of Rh2s were also significantly increased (2.3- and 3.9-fold) in the presence of inhibitors. Similar results were obtained when transcellular transport of Rh2s were determined using MDR1-overexpressing MDCKII cells in the absence or presence of cyclosporine A. Compared with WT mice, the plasma C(max) and AUC₀-∞ of Rh2s were substantially increased by 17- and 23-fold in MDR1a/b⁻/⁻ FVB mice, respectively. In the A/J mice, the oral bioavailability of Rh2s (0.94% at 5 mg/kg and 0.52% at 20 mg/kg) was substantially increased by P-gp inhibitor to 33.18 and 27.14%, respectively. As expected, deletion or inhibition of P-gp significantly increased absorption and steady-state plasma concentration of Rh2s in a mouse intestinal perfusion model. In conclusion, Rh2s is a good substrate of P-gp, and inhibition of P-gp can significantly enhance its oral bioavailability.
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77030, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yang
authors.forename: Song
authors.initials: S
authors.lastname: Gao
authors.forename: Jingrong
authors.initials: J
authors.lastname: Wang
authors.forename: Taijun
authors.initials: T
authors.lastname: Yin
authors.forename: Yang
authors.initials: Y
authors.lastname: Teng
authors.forename: Baojian
authors.initials: B
authors.lastname: Wu
authors.forename: Ming
authors.initials: M
authors.lastname: You
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Jiang
authors.forename: Ming
authors.initials: M
authors.lastname: Hu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001692:Biological Transport; D018938:Caco-2 Cells; D016572:Cyclosporine / Q000494:pharmacology; D004285:Dogs; D036145:Ginsenosides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012995:Solubility; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D036145:Ginsenosides; C055305:ginsenoside Rh2; D016572:Cyclosporine; D014700:Verapamil