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EP

epitiostanol (epitiostanol / epithioandrostanol / Thiobrestin)

✓ Approved

Ildong Pharmaceutical · AR · 小分子

什么是 epitiostanol？

epitiostanol 是一种小分子，由Ildong Pharmaceutical研发。该药已获批，用于治疗相关适应症。

药物档案

商品名epitiostanol, epithioandrostanol, Thiobrestin
公司Ildong Pharmaceutical
药物类别小分子
分子靶点AR
状态Approved
来源： ClinicalTrials.gov, Ildong Pharmaceutical

作用机制

分子靶点

epitiostanol 作用于 1 个分子靶点：

ARandrogen receptor (DHTR, AR8)
需要更深入的分析？Noah AI 可解释复杂机制并与同类药物比较。

治疗适应症

epitiostanol 针对 1 个适应症，涉及 1 个治疗领域。

治疗领域疾病/病症分期
Neoplasms benign, malignant and unspecified (incl cysts and polyps)Neoplasm malignant✓ Approved

相关研究文献

PubMedThe Journal of clinical investigation2015-12-15

Progesterone receptor membrane component-1 regulates hepcidin biosynthesis.

Li Xiang X, Rhee David K DK, Malhotra Rajeev R, Mayeur Claire C et al.

Iron homeostasis is tightly regulated by the membrane iron exporter ferroportin and its regulatory peptide hormone hepcidin. The hepcidin/ferroportin axis is considered a promising therapeutic target for the treatment of diseases of iron overload or deficiency. Here, we conducted a chemical screen in zebrafish to identify small molecules that decrease ferroportin protein levels. The chemical screen led to the identification of 3 steroid molecules, epitiostanol, progesterone, and mifepristone, which decrease ferroportin levels by increasing the biosynthesis of hepcidin. These hepcidin-inducing steroids (HISs) did not activate known hepcidin-inducing pathways, including the BMP and JAK/STAT3 pathways. Progesterone receptor membrane component-1 (PGRMC1) was required for HIS-dependent increases in hepcidin biosynthesis, as PGRMC1 depletion in cultured hepatoma cells and zebrafish blocked the ability of HISs to increase hepcidin mRNA levels. Neutralizing antibodies directed against PGRMC1 attenuated the ability of HISs to induce hepcidin gene expression. Inhibiting the kinases of the SRC family, which are downstream of PGRMC1, blocked the ability of HISs to increase hepcidin mRNA levels. Furthermore, HIS treatment increased hepcidin biosynthesis in mice and humans. Together, these data indicate that PGRMC1 regulates hepcidin gene expression through an evolutionarily conserved mechanism. These studies have identified drug candidates and potential therapeutic targets for the treatment of diseases of abnormal iron metabolism.

PMID 26657863
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PubMedJournal of pharmaceutical and biomedical analysis2015-08-08

Determination of mepitiostane metabolites in human urine by liquid chromatography/tandem mass spectrometry for sports drug testing.

Okano Masato M, Sato Mitsuhiko M, Kojima Asami A, Kageyama Shinji S

Mepitiostane (2α,3α-epithio-17β-(1-methoxycyclopentyloxy)-5α-androstane), which is a prodrug of epitiostanol (2α,3α-epitio-5α-androstane-17β-ol), is an epitiosteroid having anti-estrogenic and weak androgenic anabolic activities. The World Anti-Doping Agency prohibits the misuse of mepitiostane by athletes. Detection of the urinary metabolites epitiostanol sulfoxide and epitiostanol was studied using liquid chromatography/mass spectrometry (LC-MS) for doping control purposes. The use of LC-MS provided advantages over gas chromatography/mass spectrometry for detecting heat labile steroids because epitiostanol and epitiostanol sulfoxide were primarily pyrolized to 5α-androst-2-en-17β-ol. The method consists of enzymatic hydrolysis using β-glucuronidase (Escherichia coli), liquid-liquid extraction, and subsequent ultra-performance liquid chromatography/electrospray-tandem mass spectrometry. Epitiostanol sulfoxide was determined at urinary concentrations of 0.5-50ng/mL, recovery was 76.2-96.9%, and assay precision was calculated as 0.9-1.7% (intra-day) and 2.0-6.6% (inter-day). Epitiostanol was determined at urinary concentrations of 0.5-50ng/mL, recovery was 26.1-35.6% and assay precision was calculated as 4.1-4.6% (intra-day) and 3.3-8.5% (inter-day). The limits of detection for epitiostanol sulfoxide and epitiostanol were 0.05ng/mL and 0.10ng/mL, respectively. Epitiostanol sulfoxide and epitiostanol, as their gluco-conjugates, were identified in human urine after oral administration of 10mg mepitiostane. Epitiostanol sulfoxide and epitiostanol could be detected up to 48h and 24h after administration, respectively. The results showed that the detection window of epitiostanol is much shorter than that of epitiostanol sulfoxide. The LC-MS detection of urinary epitiostanol sulfoxide, a specific metabolite with a sulphur atom in its molecular structure, is likely to be able to identify the abuse of mepitiostane.

PMID 26247800
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PubMedCell structure and function1995-04-01

Estrogen-depleted condition induces apoptosis of rat mammary cancer cells after entering the S-phase of the cell cycle.

Watanabe Y Y, Sawada N N, Isomura H H, Satoh H H et al.

To elucidate the relationship of estrogen-depleted condition to apoptosis and tumor regression, 7,12-dimethylbenz[a]anthracene-induced mammary cancers of Sprague-Dawley rats were ovariectomized or treated with the anti-estrogenic agent epitiostanol after which proliferative activity and the incidence of apoptosis were investigated using the nick end labeling method, agarose gel electrophoresis of DNA, electron microscopy, the BrdU-labeling method and mitotic count. Tumor regression was found after 7-day treatment, and apoptosis induced by the agent on the 3rd day was clearly shown in both agarose gel electrophoresis of DNA and electron microscopy, which are two major methods used to judge apoptosis. The incidence of apoptosis revealed by the nick end labeling method reached its maximum, about threefold the control level, on the 3rd day of epitiostanol treatment compared with control tumors (P < 0.01). The incidence of the cells incorporating BrdU reached its maximum of 9.7% on the 2nd day of the treatment, while the incidence in tumors without treatment was 7.5% (P < 0.05). Subsequently, the incidence of apoptosis was reduced after 7-day treatment, and the incidence of BrdU-positive cells was significantly reduced to about 3% after 5-day treatment. The incidence of mitosis did not change until the 3rd day of the treatment and was reduced after 5-day treatment. Similarly, chronological changes of the incidences of BrdU-labeled cells, apoptotic cells and mitosis were observed in the tumors after ovariectomy. BrdU-labeled apoptotic bodies were detected in the tumors on the 3rd day in epitiostanol-treated rats that received a 6-hr bolus of BrdU before sacrifice.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID 7641294
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PubMedPharmaceutical research1992-12-01

Factors determining the intrinsic lymphatic partition rate of epitiostanol and mepitiostane.

Ichihashi T T, Takagishi Y Y, Yamada H H

Substitution of the steroid epitiostanol (EP) at position 17 with methoxycyclopentane yields the extremely liophilic mepitiostane (MP) with preferential partitioning into the lymph. Most of the MP in the lymph was associated with the core lipids of chylomicrons and very low-density lipoproteins (VLDL), as was also the case for EP. However, the dialysis velocity of EP and MP from lymph to plasma differed greatly; EP, but not MP, was transferred from the lymph to the plasma. This difference was attributed to differences in their unbound fraction in the lymph. Lymphatic transfer and the logP value of several tested steroids correlated well. Therefore, the oral EP prodrug, MP, partitioned into the lymph because of its superlipophilicity and resultant retention in the core lipids of chylomicrons and VLDL.

PMID 1488406
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PubMedPharmaceutical research1991-10-01

Intrinsic lymphatic partition rate of mepitiostane, epitiostanol, and oleic acid absorbed from rat intestine.

Ichihashi T T, Kinoshita H H, Takagishi Y Y, Yamada H H

Mepitiostane (MP), epitiostanol (EP), and oleic acid were administered to the jejunal loop of mesenteric vein- and thoracic duct-cannulated rats, and the intrinsic lymphatic partition rate (ILPR) of the absorbed compounds was directly determined. When 14C-EP was administered to the jejunal loop, recovery of unchanged EP in the mesenteric blood and the lymph was 7.9 and 0.03% of the administered dose, respectively. In contrast, following administration of 14C-MP, recovery of unchanged MP in the mesenteric blood and the lymph was 1.2 and 15.0%, respectively. Thus, following passage through the mucosal cell, 99.6% of the unchanged EP was partitioned into the blood and 0.4% into the lymph, while for unchanged MP, 7.6% was partitioned into the blood and 92.4% into the lymph. When 14C-oleic acid was administered to the jejunal loop, most of the penetrating oleic acid was incorporated into triglycerides in epithelial cells and transferred exclusively into the lymph. However, of the unchanged oleic acid, only 37.6% was partitioned into the lymph and 62.4% into the blood. The ILPR was 92.4% for MP, 0.4% for EP, and 37.6% for oleic acid. We conclude that the ILPR values indicate the true lymphotropic property of the compounds.

PMID 1796049
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PubMedXenobiotica; the fate of foreign compounds in biological systems1991-07-01

Absorption and disposition of epithiosteroids in rats (1): Route of administration and plasma levels of epitiostanol.

Ichihashi T T, Kinoshita H H, Shimamura K K, Yamada H H

1. Absorption and disposition of epitiostanol (EP) were determined following intramuscular (i.m.), intravenous (i.v.) and oral administration of 14C-epitiostanol (14C-EP) to rats. 2. When 14C-EP was administered orally, radioactivity was absorbed from the gastrointestinal tract and appeared in the systemic circulation, but no unchanged EP was detected in the plasma. EP was extensively metabolized by first-pass metabolism in the intestinal mucosa and liver, and because of the low biological activity when given orally, EP should be given by injection. 3. The EP plasma concentration/time curve following i.m. administration is analysed by a flip-flop model (ka less than kel), because the ka for EP remaining at the i.m. injection site was less than the kel for i.v. injection.

PMID 1776262
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