Characterization of ADME Properties of Diosgenin and Dioscin: Bioactive Constituents of Dioscorea villosa (Wild yam)

Dioscorea villosa (Wild yam) is native to North America. It has been widely used as a natural alternative for estrogen replacement therapy to improve women's health. Traditionally, it has also been used to treat inflammation, muscle spasm and asthma. Diosgenin and dioscin are the main pharmacologically active compounds. Dioscin is the glycoside form of diosgenin. Recent preclinical studies have shown the potential use of dioscin and diosgenin in conditions related to inflammation, cancer, diabetes, and gastrointestinal ailments. Despite the significant pharmacological properties, no reports are available on ADME properties of these compounds. The current study was carried out to determine ADME properties and their effects on major drug metabolizing enzymes (CYP 3A4, 2D6, 2C9 and 1A2). Stability was determined in simulated gastric and intestinal fluids (SGF pH 1.2 and SIF pH 6.8). Intestinal transport was evaluated using a 21 day Caco-2 culture model. Phase I and phase II metabolic stability was determined in human liver microsomes and S9 fractions, respectively. Quantitative analysis of dioscin and diosgenin was performed by UPLC-MS system. The aglycone diosgenin was stable in SGF and SIF while dioscin degraded up to 28.3% in SGF and 12.4% in SIF. In SGF, 24.2% of dioscin was converted into diosgenin while only 2.4% of diosgenin formation was seen in SIF. Diosgenin was stable in HLM but degraded in S9 fraction with a half-life of 11.3 min. In contrast, dioscin was stable in both HLM and S9 fractions. Caco-2 studies indicated that diosgenin was subjected to efflux specifically mediated by P-glycoprotein (P-gp). On the other hand, dioscin showed higher permeability across Caco-2 monolayer with no significant efflux. Diosgenin and dioscin inhibited CYP3A4 with IC₅₀ values of 8 and 30 µg/mL, respectively while other CYP enzymes were not affected. In conclusion, dioscin showed better intestinal absorption and metabolic stability compared to its aglycone diosgenin. Acknowledgements: The United States Department of Agriculture, Agricultural Research Service, Specific Cooperative Agreement No. 58 – 6408 – 02 – 1-612, the FDA “Science Based Authentication of Dietary Supplements” award number 5U01FD004246 and the National Center for Complementary and Alternative Medicines (NCCAM), the Office of Dietary Supplements (ODS) and the National Cancer Institute (NCI) Grant Number P50AT006268. References: [1] Wang Q, et al. (2002) In vitro Cell Dev Biol Anim, 42: 8 – 12. [2] Obach RS, et al. (1999) Drug Metab Dispos, 27: 1350 – 1359. [3] Madgula VL, et al. (2007) Planta Med, 73: 330 – 335