Estrogen receptor (ER) antagonist [1,4,6]

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]

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恩塞罗米芬（0-100 μM，6 小时）剂量依赖性地抑制小型和大型绵羊黄体细胞的基础和促性腺激素刺激的孕激素分泌[2]。 Enclomiphene（0-100 μg/mL，24 小时）剂量依赖性地抑制小鼠卵母细胞受精、囊胚发育和退化的速率 [3]。在原代绵羊垂体细胞中，enclomiphene（1 nM-10 μM，6 小时）剂量依赖性地降低 E2 诱导的卵泡刺激素 (FSH) 分泌抑制 [4]。

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]

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在完整或去势大鼠中，恩氯米芬（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]。口服恩氯米芬可降低血清胆固醇并将体重降低至假手术水平（每天 0.03-3 mg/kg，持续 90 天）[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]

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.

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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]

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.

[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.

Therapeutic Uses
Fertility Agents, Female
MEDICATION (VET): TO INDUCE OVULATION IN ANOVULATORY FEMALES, & TO INDUCE NORMAL MENSTRUAL CYCLING IN AMENORRHEA OR OLIGOMENORRHEA.
THE INCIDENCE OF MULTIPLE GESTATIONS IS ABOUT 8% OR SIX TIMES NORMAL BUT IS LOWER THAN WITH /HUMAN MENOPAUSAL GONADOTROPIN/ HMG. MULTIPLE BIRTHS ARE ALMOST ALWAYS TWINS; LARGER MULTIPLE GESTATIONS HAVE BEEN REPORTED RARELY. SPONTANEOUS ABORTIONS (MOSTLY EARLY MISCARRIAGES) OCCUR IN APPROX 20% OF CLOMIPHENE-INDUCED PREGNANCIES, WHICH MAY BE ONLY SLIGHTLY HIGHER THAN NORMAL BUT IS NOT HIGHER THAN AN INFERTILE POPULATION. /CLOMIPHENE CITRATE/
CLOMIPHENE CITRATE HAS ALSO BEEN USED IN MEN TO TREAT OLIGOSPERMIA ... BUT THE VALUE OF THIS TREATMENT HAS NOT YET BEEN ESTABLISHED. /CLOMIPHENE CITRATE/
For more Therapeutic Uses (Complete) data for CLOMIPHENE (10 total), please visit the HSDB record page.

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Drug Warnings
OBJECTIVE SIGNS ARE RARELY FOUND, ALTHOUGH MEASURABLE LOSS OF VISUAL ACUITY, DEFINABLE SCOTOMATA, & CHANGES IN RETINAL CELL FUNCTION HAVE BEEN REPORTED. /CLOMIPHENE CITRATE/
OTHER ADVERSE REACTIONS INCLUDE...HEADACHE, BREAST ENGORGEMENT, & ABDOMINAL BLOATING. SYMPTOMS DISAPPEAR WHEN THERAPY IS STOPPED. /CLOMIPHENE CITRATE/
SOME PHYSICIANS CONSIDER VISUAL ABNORMALITIES TO BE A CONTRAINDICATION TO FURTHER USE, WHILE OTHERS CONTINUE THERAPY WITH LOWER DOSES. ... CLOMIPHENE SHOULD NOT BE ADMIN TO PREGNANT WOMEN; THERE IS NO INDICATION FOR CLOMIPHENE THERAPY ONCE CONCEPTION HAS BEEN ACHIEVED. /CLOMIPHENE CITRATE/
SULFOBROMOPHTHALEIN RETENTION MAY BE INCR. DESMOSTEROL LEVELS ARE ELEVATED BY HIGH DOSES.
For more Drug Warnings (Complete) data for CLOMIPHENE (21 total), please visit the HSDB record page.

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Pharmacodynamics
Clomifene (previously clomiphene) is an orally administered, non steroidal, ovulatory stimulant that acts as a selective estrogen receptor modulator (SERM). Clomifene can lead to multiple ovulation, and hence increase the risk of conceiving twins. In comparison to purified FSH, the rate of ovarian hyperstimulation syndrome is low. There may be an increased risk of ovarian cancer and weight gain. Clomifene is capable of interacting with estrogen-receptor-containing tissues, including the hypothalamus, pituitary, ovary, endometrium, vagina, and cervix. It may compete with estrogen for estrogen-receptor-binding sites and may delay replenishment of intracellular estrogen receptors. Clomifene initiates a series of endocrine events culminating in a preovulatory gonadotropin surge and subsequent follicular rupture. The first endocrine event, in response to a course of clomifene therapy, is an increase in the release of pituitary gonadotropins. This initiates steroidogenesis and folliculogenesis resulting in growth of the ovarian follicle and an increase in the circulating level of estradiol. Following ovulation, plasma progesterone and estradiol rise and fall as they would in a normal ovulatory cycle.

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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]

C26H28CLNO

405.96

405.185

C, 76.92; H, 6.95; Cl, 8.73; N, 3.45; O, 3.94

15690-57-0

Enclomiphene citrate;7599-79-3;Enclomiphene hydrochloride;14158-65-7;Enclomiphene-d4 hydrochloride

1548953

Typically exists as solid at room temperature

1.1±0.1 g/cm3

509.0±50.0 °C at 760 mmHg

116.5-118
MP: 116.5-118 °C /CITRATE/

261.6±30.1 °C

0.0±1.3 mmHg at 25°C

1.588

8.01

12.47

0

2

9

29

481

0

Cl/C(/C1C=CC=CC=1)=C(\C1C=CC(OCCN(CC)CC)=CC=1)/C1C=CC=CC=1

GKIRPKYJQBWNGO-OCEACIFDSA-N

InChI=1S/C26H28ClNO/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/h5-18H,3-4,19-20H2,1-2H3/b26-25+

2-[4-[(E)-2-chloro-1,2-diphenylethenyl]phenoxy]-N,N-diethylethanamine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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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。