Both basal and gonadotropin-stimulated progesterone secretion from small and large ovine luteal cells is dose-dependently inhibited by encelomiphene (0-100 μM, 6 hours) [2]. Enclomiphene (0-100 μg/mL, 24 hours) dose-dependently suppresses the rates of mouse oocyte fertilization, blastocyst development, and degeneration [3]. In primary sheep pituitary cells, enclomiphene (1 nM-10 μM, 6 hours) dose-dependently decreases E2-induced suppression of follicle-stimulating hormone (FSH) secretion [4].

In intact or castrated rats, enclomiphene (subcutaneous injection, 0.25 and 0.5 mg/animal, daily) suppresses spermatogenesis and lowers serum levels of testosterone and luteinizing hormone (LH) [5]. Enclomiphene lowers serum cholesterol and reduces body weight to sham levels when taken orally (0.03–3 mg/kg daily for 90 days) [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.

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]. Rodriguez KM, et al. Enclomiphene citrate for the treatment of secondary male hypogonadism. Expert Opin Pharmacother. 2016 Aug;17(11):1561-7.
[2]. M S Opsahl, et al. 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]. G E Schmidt, et al. 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]. E S Huang, et al. 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]. R Weissenberg, et al. 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]. R T Turner, et al. 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.

C26H28CLNO

405.96

405.185

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

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

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)