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United States Department of Agriculture

Agricultural Research Service

Research Project: DISCOVERY AND DEVELOPMENT OF NATURAL PRODUCTS FOR PHARMACEUTICAL AND AGROCHEMICAL APPLICATIONS

Location: Natural Products Utilization Research

Title: Characterization of in vitro ADME properties of diosgenin and dioscin from dioscorea villosa

Authors
item Manda, Vamshi -
item Bharathi, Avula -
item Ali, Zulfiqar -
item Wang, Yanhong -
item Smillie, Troy -
item Khan, Ikhlas -
item Khan, Shabana -

Submitted to: Planta Medica
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: July 8, 2013
Publication Date: August 22, 2013
Citation: Manda, V.K., Bharathi, A., Ali, Z., Wang, Y., Smillie, T.J., Khan, I.A., Khan, S.I. 2013. Characterization of in vitro ADME properties of diosgenin and dioscin from dioscorea villosa. Planta Medica. 79:1421-1428.

Interpretive Summary: Traditionally, Dioscorea villosa (wild yam) root and rhizome extract has been used to relieve symptoms associated with menopause and rheumatoid arthritis. Literature suggests that the two main ingredients found in wild yam are diosgenin and dioscin. The current study focuses on studying the absorption, distribution, metabolism, and excretion (ADME) properties of these two compounds using in vitro based assays. Since the wide use of this plant, the inhibitory potential of diosgenin and dioscin against major enzymes involved in drug-drug interactions were also determined. Dioscin was unstable in gastric and intestinal fluids. Diosgenin and dioscin showed moderate absorption rates across intestinal monolayers. This is the first report to compare the ADME properties of two major compounds present in wild yam. Diosgenin and dioscin had weak interactions with drug metabolizing enzymes indicative of safety, if used in combination with other drugs.

Technical Abstract: Dioscorea villosa (wild yam) is native to North America and has been widely used as a natural alternative for estrogen replacement therapy to improve women’s health as well as to treat inflammation, muscle spasm and asthma. Diosgenin and dioscin (glycoside form of diosgenin) are reported to be the pharmacologically active compounds. Despite the reports of significant pharmacological properties of dioscin and diosgenin in conditions related to inflammation, cancer, diabetes, and gastrointestinal ailments, no reports are available on ADME properties of these compounds. This study was carried out to determine ADME properties of diosgenin and dioscin and their effects on major drug metabolizing enzymes (CYP 3A4, 2D6, 2C9 and 1A2). The stability was determined in simulated gastric and intestinal fluids (SGF, pH 1.2 and SIF, pH 6.8) and intestinal transport was evaluated in Caco-2 model. Phase I and phase II metabolic stability was determined in human liver microsomes (HLM) and S9 fractions, respectively. Quantitative analysis of dioscin and diosgenin was performed by UPLC-MS system. Dioscin degraded up to 28.3% in SGF and 12.4% in SIF which could be accounted for its conversion to diosgenin (24.2%. in SGF and 2.4% in SIF). The depletion of diosgenin in SGF and SIF was <10%. Diosgenin was stable in HLM but disappeared in S9 fraction with a half-life of 11.3 minutes. In contrast, dioscin was stable in both HLM and S9 fractions. Dioscin showed higher permeability across Caco-2 monolayer with no significant efflux while diosgenin was subjected to efflux mediated by P-glycoprotein (P-gp). Diosgenin and dioscin inhibited CYP3A4 with IC50 values of 9 and 29 µg/mL, respectively, while other CYP enzymes were not affected. In conclusion, dioscin showed better intestinal permeability. Conversion of dioscin to diosgenin was observed in both gastric and intestinal fluids. No phase I metabolism was detected for both compounds. The disappearance of diosgenin in S9 fraction indicated phase II metabolism.

Last Modified: 12/25/2014
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