ER/estrogen receptor

Enclomiphene citrate（0-100 μM，6 小时）以剂量依赖性方式抑制促性腺激素和基础刺激的小规模和大规模绵羊黄体细胞黄体酮分泌[2]。 Enclomiphene citrate（0-100 μg/mL，24 小时）剂量依赖性地抑制小鼠卵母细胞中囊胚形成、退化和受精的速率[3]。 Enclomiphene citrate（1 nM-10 μM，6 小时）剂量依赖性地减少 E2 诱导的原代绵羊垂体细胞中促卵泡激素 (FSH) 分泌的抑制作用[4]。

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Enclomiphene (10⁻⁷ M) 显著增加绵羊小黄体细胞的基础孕酮分泌，但对大黄体细胞无影响；在LH存在下，可增强两类细胞的孕酮分泌 [2]
Enclomiphene (10⁻⁵ M) 对小鼠胚胎从两细胞期至囊胚期的体外发育无影响 [3]
Enclomiphene (10⁻⁸–10⁻⁶ M) 阻断雌二醇对绵羊垂体细胞LH/FSH分泌的抑制作用，且无内在激动活性 [4]
Enclomiphene (10⁻⁵ M) 降低大鼠子宫组织中雌二醇刺激的孕酮受体表达 [6]

在完整或去势大鼠中，克罗米芬柠檬酸盐（皮下注射，0.25 和 0.5 mg/动物，每日）抑制精子发生并降低睾酮和黄体生成素 (LH) 的血清水平[5]。当以每天 0.03-3 mg/kg 的剂量口服给药 90 天时，恩氯米芬柠檬酸盐可将血清胆固醇和体重降低至假手术水平 [6]。

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妊娠小鼠给予enclomiphene (1 mg/kg) 后，体内受精的囊胚形成与着床率无变化 [3]
未成熟雄性大鼠给予enclomiphene (0.5 mg/kg/天 × 10天) 后，睾丸重量和血清睾酮升高 [5]
卵巢切除大鼠给予enclomiphene (0.15 mg/kg/天 × 4天) 后，血清LH/FSH升高，并拮抗雌二醇诱导的子宫增重 [6]

孕酮分泌实验：通过淘析法分离绵羊小/大黄体细胞，用enclomiphene (10⁻⁷ M) ± LH (10 ng/ml) 处理3小时，放射免疫法检测培养基孕酮 [2]
垂体促性腺激素分泌实验：绵羊垂体细胞培养72小时后，暴露于enclomiphene (10⁻⁸–10⁻⁶ M) ± 雌二醇 (10⁻⁹ M)，RIA法检测上清液LH/FSH [4]
孕酮受体表达实验：取卵巢切除大鼠子宫组织，与enclomiphene (10⁻⁵ M) ± 雌二醇共培养，免疫印迹法分析受体水平 [6]

Mouse embryo development: Female mice received enclomiphene (1 mg/kg, route unspecified) on gestation days 1–2. Embryos were collected on day 3 for blastocyst assessment [3]
Immature rat testosterone study: Prepubertal male rats were injected subcutaneously with enclomiphene (0.5 mg/kg/day in saline) for 10 days. Testes and serum were collected for analysis [5]
Ovariectomized rat model: Rats received subcutaneous enclomiphene (0.15 mg/kg/day in sesame oil) for 4 days ± estradiol benzoate (10 μg/kg). Uterine weight and serum hormones were measured [6]

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Animal/Disease Models: 21-day-old Charles River male rats [5]
Doses: 0.25 and 0.5 mg/rat, one time/day for 24 days.
Route of Administration: subcutaneous injection.
Experimental Results: LH and testosterone levels in serum diminished.

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Animal/Disease Models: OVX (ovariectomy) rat model [6]
Doses: 0.03, 1 and 3 mg/kg daily for 90 days. Method of
Route of Administration: Oral administration
Experimental Results: diminished body weight to sham levels and diminished serum cholesterol. demonstrated dose-dependent effects on the proximal tibia, with BMD and BMC approaching post-treatment sham levels.

Absorption, Distribution and Excretion
Based on early studies with 14 C-labeled clomifene, the drug was shown to be readily absorbed orally in humans.
Based on early studies with 14C-labeled clomiphene citrate, the drug was shown to be readily absorbed orally in humans and excreted principally in the feces. Mean urinary excretion was approximately 8% with fecal excretion of about 42%.
SC DOSE OF (14)C CLOMIPHENE CITRATE...WAS DISTRIBUTED IN TISSUES OF FEMALE GUINEA PIG NEONATES... ESTROGENIC-RESPONSIVE TISSUES SHOWED HIGH AFFINITY FOR (14)C. LEVELS OF (14)C...CONSTANT IN UTERUS...THOSE IN OVARIES & PLASMA DECLINED...IN ADRENALS INCR. /CLOMIPHENE CITRATE/
ABOUT ONE-HALF OF THE INGESTED DOSE IS EXCRETED IN FIVE DAYS; TRACES APPEAR IN THE FECES UP TO SIX WEEKS AFTER ADMIN. /CLOMIPHENE CITRATE/
Clomiphene is well absorbed following oral administration. The drug and its metabolites are eliminated primarily in the feces and to a lesser extent in the urine. The rather long plasma half-life (approximately 5 to 7 days) is due largely to plasma protein binding, enterophepatic circulation, and accumulation in fatty tissues. Active metabolites with long half-lives also may be produced.

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Metabolism / Metabolites
Hepatic
INCUBATION OF THE NONSTEROIDAL ANTIESTROGEN CLOMIPHENE WITH RAT LIVER MICROSOMES RESULTED IN THE FORMATION OF THE 4-HYDROXY-, N-DESETHYL-, & N-OXIDE METABOLITES, IN QUALITATIVE CONTRAST TO RESULTS PREVIOUSLY OBTAINED ANALOGOUSLY WITH RABBIT MICROSOMES IN WHICH ONLY THE FIRST 2 METABOLITES WERE DETECTED. ORAL ADMIN OF CLOMIPHENE RESULTED IN NO DETECTABLE URINARY ELIMINATION OF THE DRUG OR ITS METABOLITES. 4-HYDROXYCLOMIPHENE WAS THE SOLE DETECTABLE ELIMINATION PRODUCT IN FECAL EXTRACTIONS.
Hepatic

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Biological Half-Life
5-7 days

Toxicity Summary
Clomifene has both estrogenic and anti-estrogenic properties, but its precise mechanism of action has not been determined. Clomifene appears to stumulate the release of gonadotropins, follicle-stimulating hormone (FSH), and leuteinizing hormone (LH), which leads to the development and maturation of ovarian follicle, ovulation, and subsequent development and function of the coprus luteum, thus resulting in pregnancy. Gonadotropin release may result from direct stimulation of the hypothalamic-pituitary axis or from a decreased inhibitory influence of estrogens on the hypothalamic-pituitary axis by competing with the endogenous estrogens of the uterus, pituitary, or hypothalamus. Clomifene has no apparent progestational, androgenic, or antrandrogenic effects and does not appear to interfere with pituitary-adrenal or pituitary-thyroid function.

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Toxicity Data
The acute oral LD₅₀ of clomifene is 1700 mg/kg in mice and 5750 mg/kg in rats. The toxic dose in humans is not known. Toxic effects accompanying acute overdosage of clomifene have not been reported. Signs and symptoms of overdosage as a result of the use of more than the recommended dose during clomifene therapy include nausea, vomiting, vasomotor flushes, visual blurring, spots or flashes, scotomata, ovarian enlargement with pelvic or abdominal pain.

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6420009 women TDLo oral 73500 ug/kg/3W BEHAVIORAL: WAKEFULNESS; BEHAVIORAL: TOXIC PSYCHOSIS American Journal of Psychiatry., 154(1169), 1997
6420009 man TDLo oral 10 mg/kg/2W-I BEHAVIORAL: HALLUCINATIONS, DISTORTED PERCEPTIONS; BEHAVIORAL: TOXIC PSYCHOSIS; BEHAVIORAL: IRRITABILITY American Journal of Psychiatry., 154(1169), 1997

[1]. Enclomiphene citrate for the treatment of secondary male hypogonadism. Expert Opin Pharmacother. 2016 Aug;17(11):1561-7.

[2]. Effects of enclomiphene and zuclomiphene on basal and gonadotrophin-stimulated progesterone secretion by isolated subpopulations of small and large ovine luteal cells. Hum Reprod. 1996 Jun;11(6):1250-5.

[3]. The effects of enclomiphene and zuclomiphene citrates on mouse embryos fertilized in vitro and in vivo. Am J Obstet Gynecol. 1986 Apr;154(4):727-36.

[4]. Estrogenic and antiestrogenic effects of enclomiphene and zuclomiphene on gonadotropin secretion by ovine pituitary cells in culture. Endocrinology. 1983 Feb;112(2):442-8.

[5]. The effect of clomiphene citrate and its Zu or En isomers on the reproductive system of the immature male rat. Andrologia. 1992 May-Jun;24(3):161-5.

[6]. Differential responses of estrogen target tissues in rats including bone to clomiphene, enclomiphene, and zuclomiphene. Endocrinology. 1998 Sep;139(9):3712-20.

Clomiphene Citrate can cause cancer and developmental toxicity according to state or federal government labeling requirements.
Enclomiphene Citrate is the orally bioavailable citrate salt of enclomiphene, the trans-isomer of the nonsteroidal triphenylethylene compound clomiphene, with tissue-selective estrogenic and antiestrogenic activities. As a selective estrogen receptor modulator (SERM), enclomiphene binds to hypothalamic estrogen receptors, blocking the negative feedback of endogenous estrogens and stimulating the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus; released GnRH subsequently stimulates the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary, resulting in ovulation. In addition, this agent may bind to estrogen receptors on breast cancer cells, resulting in the inhibition of estrogen-stimulated proliferation in susceptible cell populations.
The trans or (E)-isomer of clomiphene.
See also: Clomiphene Citrate (annotation moved to).

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Enclomiphene is the trans-isomer of clomiphene and acts as a selective estrogen receptor antagonist in the pituitary/hypothalamus, increasing gonadotropin and testosterone secretion in men with secondary hypogonadism [1]
Unlike zuclomiphene, enclomiphene lacks estrogenic activity in bone tissue and does not affect bone mineral density in rats [6]

C32H36CLNO8

598.089

597.213

C, 64.26; H, 6.07; Cl, 5.93; N, 2.34; O, 21.40

7599-79-3

Enclomiphene;15690-57-0;Clomiphene-d5 citrate;1217200-17-3;Enclomiphene hydrochloride;14158-65-7

6420009

White to off-white solid powder

509ºC at 760mmHg

261.6ºC

5.314

144.6

4

9

14

42

708

0

Cl/C(/C1C=CC=CC=1)=C(\C1C=CC=CC=1)/C1C=CC(=CC=1)OCCN(CC)CC.OC(C(=O)O)(CC(=O)O)CC(=O)O

PYTMYKVIJXPNBD-BTKVJIOYSA-N

InChI=1S/C26H28ClNO.C6H8O7/c1-3-28(4-2)19-20-29-24-17-15-22(16-18-24)25(21-11-7-5-8-12-21)26(27)23-13-9-6-10-14-23;7-3(8)1-6(13,5(11)12)2-4(9)10/h5-18H,3-4,19-20H2,1-2H3;13H,1-2H2,(H,7,8)(H,9,10)(H,11,12)/b26-25+

2-[4-[(E)-2-chloro-1,2-diphenylethenyl]phenoxy]-N,N-diethylethanamine;2-hydroxypropane-1,2,3-tricarboxylic acid

ICI-46476; ICI 46476; ICI46476; Enclomiphene citrate; 7599-79-3; trans-Clomiphene citrate; Enclomid; Clomiphene b citrate; (E)-Clomiphene citrate; J303A6U9Y6; DTXSID80226887; RMI-16289; RMI 16289; RMI16289; (E)-Clomiphene citrate; Androxal; Enclomiphene citrate; Enclomid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮和光照。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~100 mg/mL (~167.2 mM)
Ethanol: ~2 mg/mL (~3.3 mM)

配方 1 中的溶解度: ≥ 0.83 mg/mL (1.39 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 8.3 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 0.83 mg/mL (1.39 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 8.3 mg/mL 澄清 DMSO 储备液加入 900 μL 20% SBE-β-CD 生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 0.83 mg/mL (1.39 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 8.3 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。