Download PDF
Planta Med 2019; 85(04): 347-355
DOI: 10.1055/a-0806-7673
Pharmacokinetic Investigations
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Pharmacokinetics of Prenylflavonoids following Oral Ingestion of Standardized Epimedium Extract in Humans

Yi Ling Teo   *
1   Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
,
Wei Fun Cheong   *
1   Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
,
Amaury Cazenave-Gassiot
2   Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
,
Shanshan Ji
3   Life Science Institute, National University of Singapore, Singapore
,
Susan Logan
4   Department of Obstetrics & Gynaecology, National University Hospital, Singapore
5   University Medicine Cluster, National University Health System, Singapore
,
Zhi Xing Kelvin Lee
4   Department of Obstetrics & Gynaecology, National University Hospital, Singapore
,
Jun Li
1   Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
,
Kok Yong Seng
6   Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
,
Lawrence Soon-U Lee
5   University Medicine Cluster, National University Health System, Singapore
7   Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
,
Eu Leong Yong
1   Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
4   Department of Obstetrics & Gynaecology, National University Hospital, Singapore
5   University Medicine Cluster, National University Health System, Singapore
› Author Affiliations
Further Information

Publication History

received 31 July 2018
revised 08 November 2018

accepted 19 November 2018

Publication Date:
06 December 2018 (online)

    Permissions and Reprints

Abstract

Leaves of the Epimedium plant are traditionally consumed for bone health and other indications. The aim of this study was to establish the safety and pharmacokinetics of the metabolites of prenylflavonoids (icariin, icariside I, icariside II, icaritin, and desmethylicaritin) following single doses of a defined Epimedium prenylflavonoid extract in humans. A single oral dose of 370, 740, or 1110 mg of a standardized Epimedium prenylflavonoid extract was administered to 30 healthy male subjects in a randomized, placebo-controlled trial. Serum samples were collected over a 48-h period and analyzed by liquid chromatography-tandem mass spectrometry and non-compartmental pharmacokinetic modelling. Epimedium prenylflavonoid extracts were well tolerated and no adverse effects were observed. The principle metabolites detected in the serum were icariside II and desmethylicaritin. Icariside II had a T max of between 4.1 – 4.3 h, reaching a maximum AUC0→∞ of 23.0 (17.5, 29.9) h×ng/mL (median [IQR: interquartile range]) with the highest dose of the Epimedium prenylflavonoid. On the other hand, desmethylicaritin had a delayed T max of 24.1 – 24.4 h and reached a maximum AUC0→∞ of 126.1 (62.4, 202.9) h×ng/mL. The median maximum plasma concentration and AUC0→∞ of desmethyliciaritin showed an increase with higher doses of the Epimedium prenylflavonoid (p < 0.05). Icariin, icariside I, and icaritin levels were below detection limits. Levels of Epimedium prenylflavonoid metabolites observed in this study were consistent with levels demonstrated to have anti-osteoporotic effects in cellular and animal studies. Coupled with the favorable safety profile of the extract observed, further studies are required to explore the utility of Epimedium prenylflavonoid extracts to prevent osteoporosis in postmenopausal women.

Key words

pharmacokinetics - clinical trial - prenylflavonoids - Epimedium spp. - Berberidaceae - liquid chromatography-tandem mass spectrometry

* Co-first authors.


Supporting Information

    The coefficient of variance of TQC and PQC, intra- and interday accuracy and precision of the method, and matrix effects on the five prenylflavonoids are available as Supporting Information.

  • Supporting Information
 

  • References

  • 1 Indran IR, Liang RL, Min TE, Yong EL. Preclinical studies and clinical evaluation of compounds from the genus Epimedium for osteoporosis and bone health. Pharmacol Ther 2016; 162: 188-205
    CrossrefPubMedGoogle Scholar
  • 2 Wang Z, Wang D, Yang D, Zhen W, Zhang J, Peng S. The effect of icariin on bone metabolism and its potential clinical application. Osteoporos Int 2018; 29: 535-544
    CrossrefPubMedGoogle Scholar
  • 3 Xi HR, Ma HP, Yang FF, Gao YH, Zhou J, Wang YY, Li WY, Xian CJ, Chen KM. Total flavonoid extract of Epimedium herb increases the peak bone mass of young rats involving enhanced activation of the AC10/cAMP/PKA/CREB pathway. J Ethnopharmacol 2018; 223: 76-87
    CrossrefPubMedGoogle Scholar
  • 4 Xiong W, Chen Y, Wang Y, Liu J. Roles of the antioxidant properties of icariin and its phosphorylated derivative in the protection against duck virus hepatitis. BMC Vet Res 2014; 10: 226
    CrossrefPubMedGoogle Scholar
  • 5 Zhang WP, Bai XJ, Zheng XP, Xie XL, Yuan ZY. Icariin attenuates the enhanced prothrombotic state in atherosclerotic rabbits independently of its lipid-lowering effects. Planta Med 2013; 79: 731-736
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Indran IR, Zhang SJ, Zhang ZW, Sun F, Gong Y, Wang X, Li J, Erdelmeier CA, Koch E, Yong EL. Selective estrogen receptor modulator effects of Epimedium extracts on breast cancer and uterine growth in nude mice. Planta Med 2014; 80: 22-28
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Sun F, Zhang ZW, Tan EM, Lim ZLR, Li Y, Wang XC, Chua SE, Li J, Cheung E, Yong EL. Icaritin suppresses development of neuroendocrine differentiation of prostate cancer through inhibition of IL-6/STAT3 and Aurora kinase A pathways in TRAMP mice. Carcinogenesis 2016; 37: 701-711
    CrossrefPubMedGoogle Scholar
  • 8 Yap S, Shen P, Butler M, Gong Y, Loy C, Yong E. New estrogenic prenylflavone from Epimedium brevicornum inhibits the growth of breast cancer cells. Planta Med 2005; 71: 114-119
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Stearn WT. The Genus Epimedium and other herbaceous Berberidaceae. Portland: Timber Press, Incorporated; 2002
    Google Scholar
  • 10 Pharmacopoeia of The Peopleʼs Republic of China (English edition). Beijing, China: Chinese Medical Science Press; 2010
    Google Scholar
  • 11 Zhang CZ, Wang SX, Zhang Y, Chen JP, Liang XM. In vitro estrogenic activities of Chinese medicinal plants traditionally used for the management of menopausal symptoms. J Ethnopharmacol 2005; 98: 295-300
    CrossrefPubMedGoogle Scholar
  • 12 Zhang G, Qin L, Shi Y. Epimedium-derived phytoestrogen flavonoids exert beneficial effect on preventing bone loss in late postmenopausal women: a 24-month randomized, double-blind and placebo-controlled trial. J Bone Miner Res 2007; 22: 1072-1079
    CrossrefPubMedGoogle Scholar
  • 13 Ma H, He X, Yang Y, Li M, Hao D, Jia Z. The genus Epimedium: an ethnopharmacological and phytochemical review. J Ethnopharmacol 2011; 134: 519-541
    CrossrefPubMedGoogle Scholar
  • 14 Meng FH, Li YB, Xiong ZL, Jiang ZM, Li FM. Osteoblastic proliferative activity of Epimedium brevicornum Maxim. Phytomedicine 2005; 12: 189-193
    CrossrefPubMedGoogle Scholar
  • 15 Lim R, Li L, Chew N, Yong EL. The prenylflavonoid Icaritin enhances osteoblast proliferation and function by signal transducer and activator of transcription factor 3 (STAT-3) regulation of C-X-C chemokine receptor type 4 (CXCR4) expression. Bone 2017; 105: 122-133
    CrossrefPubMedGoogle Scholar
  • 16 Tan EM, Li L, Indran IR, Chew N, Yong EL. TRAF6 mediates suppression of osteoclastogenesis and prevention of ovariectomy-induced bone loss by a novel prenylflavonoid. J Bone Miner Res 2017; 32: 846-860
    CrossrefPubMedGoogle Scholar
  • 17 Shen P, Wong SP, Li J, Yong EL. Simple and sensitive liquid chromatography-tandem mass spectrometry assay for simultaneous measurement of five Epimedium prenylflavonoids in rat sera. J Chromatogr B Analyt Technol Biomed Life Sci 2009; 877: 71-78
    CrossrefPubMedGoogle Scholar
  • 18 Nian H, Ma MH, Nian SS, Xu LL. Antiosteoporotic activity of icariin in ovariectomized rats. Phytomedicine 2009; 16: 320-326
    CrossrefPubMedGoogle Scholar
  • 19 Ming LG, Chen KM, Xian CJ. Functions and action mechanisms of flavonoids genistein and icariin in regulating bone remodeling. J Cell Physiol 2013; 228: 513-521
    CrossrefPubMedGoogle Scholar
  • 20 Wong SP, Shen P, Lee L, Li J, Yong EL. Pharmacokinetics of prenylflavonoids and correlations with the dynamics of estrogen action in sera following ingestion of a standardized Epimedium extract. J Pharm Biomed Anal 2009; 50: 216-223
    CrossrefPubMedGoogle Scholar
  • 21 Wu H, Kim M, Han J. Icariin metabolism by human intestinal microflora. Molecules 2016; 21: 1158
    CrossrefPubMedGoogle Scholar
  • 22 Coldham NG, Zhang AQ, Key P, Sauer MJ. Absolute bioavailability of [14C] genistein in the rat; plasma pharmacokinetics of parent compound, genistein glucuronide and total radioactivity. Eur J Drug Metab Pharmacokinet 2002; 27: 249-258
    CrossrefPubMedGoogle Scholar
  • 23 Wang ZQ, Lou YJ. Proliferation-stimulating effects of icaritin and desmethylicaritin in MCF-7 cells. Eur J Pharmacol 2004; 504: 147-153
    CrossrefPubMedGoogle Scholar
  • 24 Wang ZQ, Weber N, Lou YJ, Proksch P. Prenylflavonoids as nonsteroidal phytoestrogens and related structure-activity relationships. ChemMedChem 2006; 1: 482-488
    CrossrefPubMedGoogle Scholar
  • 25 Ye HY, Lou YJ. Estrogenic effects of two derivatives of icariin on human breast cancer MCF-7 cells. Phytomedicine 2005; 12: 735-741
    CrossrefPubMedGoogle Scholar
  • 26 Wo YB, Zhu DY, Hu Y, Wang ZQ, Liu J, Lou YJ. Reactive oxygen species involved in prenylflavonoids, icariin and icaritin, initiating cardiac differentiation of mouse embryonic stem cells. J Cell Biochem 2008; 103: 1536-1550
    CrossrefPubMedGoogle Scholar
  • 27 Chen CC, Tsai PC, Wei BL, Chiou WF. 8-Prenylkaempferol suppresses inducible nitric oxide synthase expression through interfering with JNK-mediated AP-1 pathway in murine macrophages. Eur J Pharmacol 2008; 590: 430-436
    CrossrefPubMedGoogle Scholar
  • 28 Kim JH, Lee G, Cho YL, Kim CK, Han S, Lee H, Choi JS, Choe J, Won MH, Kwon YG, Ha KS, Kim YM. Desmethylanhydroicaritin inhibits NF-kappaB-regulated inflammatory gene expression by modulating the redox-sensitive PI3K/PTEN/Akt pathway. Eur J Pharmacol 2009; 602: 422-431
    CrossrefPubMedGoogle Scholar
  • 29 Wang XL, Wang N, Zheng LZ, Xie XH, Yao D, Liu MY, Yao ZH, Dai Y, Zhang G, Yao XS, Qin L. Phytoestrogenic molecule desmethylicaritin suppressed adipogenesis via Wnt/beta-catenin signaling pathway. Eur J Pharmacol 2013; 714: 254-260
    CrossrefPubMedGoogle Scholar
  • 30 Peng S, Zhang G, Zhang BT, Guo B, He Y, Bakker AJ, Pan X, Zhen W, Hung L, Qin L, Leung WN. The beneficial effect of icaritin on osteoporotic bone is dependent on the treatment initiation timing in adult ovariectomized rats. Bone 2013; 55: 230-240
    CrossrefPubMedGoogle Scholar
  • 31 Yap SP, Shen P, Butler MS, Gong Y, Loy CJ, Yong EL. New estrogenic prenylflavone from Epimedium brevicornum inhibits the growth of breast cancer cells. Planta Med 2005; 71: 114-119
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Yap SP, Shen P, Li J, Yong EL, Lee LS. Molecular and pharmacodynamic properties of estrogenic extracts from the traditional Chinese medicinal herb, Epimedium . J Ethnopharmacol 2007; 113: 218-224
    CrossrefPubMedGoogle Scholar
  • 33 Tiong CT, Chen C, Zhang SJ, Li J, Soshilov A, Denison MS, Lee LS, Tam VH, Wong SP, Xu HE, Yong EL. A novel prenylflavone restricts breast cancer cell growth through AhR-mediated destabilization of ERalpha protein. Carcinogenesis 2012; 33: 1089-1097
    CrossrefPubMedGoogle Scholar
  • 34 Shen P, Guo BL, Gong Y, Hong DY, Hong Y, Yong EL. Taxonomic, genetic, chemical and estrogenic characteristics of Epimedium species. Phytochemistry 2007; 68: 1448-1458
    CrossrefPubMedGoogle Scholar