Zuclomiphene acts as an estrogen receptor antagonist, binding to cytoplasmic and nuclear estrogen receptors [3]

In chick oviduct preparations, Zuclomiphene exhibits anti-estrogenic activity by competing with estrogen for binding to cytoplasmic and nuclear estrogen receptors. It inhibits estrogen-induced responses in the oviduct, as demonstrated by reduced estrogen-dependent biological activity [3]

In male mice, administration of Zuclomiphene (100 μg/day, subcutaneous injection) for 28 days results in a significant increase in testis weight compared to controls. It also leads to an increase in epididymal weight and affects sperm parameters, with changes in sperm count and motility. Additionally, it modulates reproductive tissue morphology, including alterations in seminiferous tubule structure [1]

In experiments with chick oviduct cytoplasmic and nuclear fractions, Zuclomiphene is incubated with these fractions in the presence of radiolabeled estrogen. The binding of Zuclomiphene to estrogen receptors is assessed by measuring the displacement of radiolabeled estrogen, allowing quantification of its affinity for the receptors [3]

For male mice studies, adult male mice are subcutaneously injected with Zuclomiphene at a dose of 100 μg/day for 28 days. Control groups receive vehicle injections. At the end of the treatment period, mice are euthanized, and reproductive tissues (testes, epididymides) are harvested for weight measurement, histological analysis, and sperm parameter evaluation [1]

Absorption, Distribution and Excretion
Based on early studies of clomiphene citrate labeled with 14C, this drug is readily absorbed orally in humans. Based on early studies of clomiphene citrate labeled with 14C, this drug is readily absorbed orally in humans and is primarily excreted via feces. The average urinary excretion rate is approximately 8%, and the fecal excretion rate is approximately 42%. Subcutaneous injection of clomiphene citrate labeled with 14C…distributed in the tissues of female newborn guinea pigs…estrogen-responsive tissues showed a high affinity for 14C. (14)C levels remained stable in the uterus…decreased in the ovaries and plasma…increased in the adrenal glands. /clomiphene citrate/ Approximately half of the ingested dose was excreted within five days; trace amounts of the drug remained in the feces for up to six weeks after administration. /Clomiphene Citrate/
Clomiphene is well absorbed after oral administration. The drug and its metabolites are primarily excreted in feces, with a small amount excreted in urine. The relatively long plasma half-life (approximately 5 to 7 days) is mainly due to plasma protein binding, enterohepatic circulation, and accumulation in adipose tissue. Long-lived active metabolites may also be produced.

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Metabolism/Metabolites
Hepatic
Incubation of the nonsteroidal anti-estrogenic drug clomiphene with rat liver microsomes resulted in the formation of 4-hydroxy, N-deethyl, and N-oxide metabolites, in stark contrast to previous similar experiments using rabbit microsomes, in which only the first two metabolites were detected. No urinary excretion of the drug or its metabolites was detected after oral administration of clomiphene. 4-hydroxyclomiphene was the only detectable elimination product in the fecal extract.

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Biological half-life
5-7 days In healthy volunteers, after a single oral dose of clomiphene citrate (which contains the isomer zuclomiphene), the elimination half-life of zuclomiphene was longer than that of the other isomer (enclomiphene). It persisted in plasma for a longer period of time and was still detectable several weeks after administration [2]

Hepatotoxicity
Information regarding serum transaminase levels during clomiphene treatment is limited because clomiphene is typically used only at low doses for short periods. Mild elevations in serum enzymes have been reported in a small number of patients taking clomiphene, but there is no conclusive evidence that it causes specific, clinically significant liver damage. Medications used to treat female infertility often work by stimulating ovarian follicles, which can lead to ovarian hyperstimulation syndrome (OHSS), sometimes accompanied by elevated serum enzymes and even jaundice. This syndrome typically occurs 4 to 14 days after ovarian stimulation with gonadotropins or clomiphene and is characterized by abdominal pain and distension, accompanied by ascites, enlarged ovaries, and ovarian cysts. Significant fluid shifts may occur, leading to hemoconcentration and rapid onset of severe ascites and pleural effusion. Liver dysfunction is present in 25% to 40% of patients with OHSS, typically manifested as mild to moderate elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), while serum bilirubin and alkaline phosphatase levels are not significantly elevated or absent. Liver function abnormalities usually return to normal as OHSS subsides, typically within 2 to 3 weeks of onset. Severe OHSS can be life-threatening, but death is usually due to dehydration, shock, and sepsis, rather than liver failure. In typical cases of abnormal liver enzymes, liver histology shows nonspecific changes, including sinusoidal dilatation, mild fat accumulation, and focal inflammatory infiltration dominated by macrophages and lymphocytes. The probability of developing ovarian hyperstimulation syndrome (OHSS) is lower with clomiphene use compared to ovulation induced by human chorionic gonadotropin (hCG). Probability score: C (likely a cause of clinically significant liver damage in ovarian hyperstimulation syndrome). Effects during pregnancy and lactation ◉ Overview of use during lactation: A small amount of clomiphene was detected in the breast milk of a woman. Multiple studies have found that clomiphene suppresses lactation in women who do not wish to breastfeed. Its mechanism of action appears to be a reduction in serum prolactin levels, particularly the peak prolactin level after stimulation. Clomiphene may interfere with lactation in breastfeeding mothers.
◉ Effects on breastfed infants
A woman taking 2.04 mg/kg clomiphene daily breastfed part-time. No adverse reactions were observed in her infant.
◉ Effects on lactation and breast milk
A double-blind study compared the effects of clomiphene 50 mg daily for 10 days (n = 110), 100 mg daily for 5 days (n = 26), and placebo (n = 41) on inhibiting lactation and relieving pain and breast engorgement in non-lactating mothers. According to participants, both doses of clomiphene were superior to placebo, but the 100 mg daily dose was slightly better than the 50 mg daily dose.
A study compared the effects of clomiphene 100 mg daily for 5 days (n = 60) versus placebo (n = 30) on inhibiting lactation and relieving breast engorgement symptoms. According to physician observers, starting clomiphene within 12 hours postpartum was superior to starting it 12 hours or longer postpartum in all indicators; both treatment methods were superior to mechanical measures alone, such as breast binding. A randomized trial compared the effects of clomiphene 50 mg twice daily for 14 days (n=15), bromocriptine 2.5 mg twice daily for 14 days (n=15), diethylstilbestrol 5 mg three times daily for 14 days (n=15), testosterone propionate 75 mg intramuscularly once (n=15), and placebo three times daily orally (n=15) on reducing postpartum serum prolactin levels and decreasing lactation. After three days of treatment, serum prolactin levels in the clomiphene group decreased to 65% of baseline, while those in the bromocriptine group only decreased to 35%. Clomiphene was also less effective than bromocriptine in inhibiting lactation and relieving breast engorgement symptoms. A study compared the effects of clomiphene 100 mg/day for 7 days starting on postpartum day 1 (n=10) with a placebo (n=12). The results showed that clomiphene was not more effective than the placebo in suppressing lactation or lowering serum prolactin levels. Women who did not wish to breastfeed during the first week postpartum received either clomiphene 50 mg/day twice daily (n=10) or a placebo (n=10). Women taking clomiphene did not experience elevated serum prolactin levels above baseline while using a breast pump; women taking the placebo experienced normal post-stimulation increases in serum prolactin. A total of 80 postpartum women participated in the study. 40 women took clomiphene 50 mg/day twice daily for 5 days starting on postpartum day 1; 20 women took clomiphene 50 mg twice daily for 5 days starting on postpartum day 4; and the remaining 20 women received a placebo. All postpartum women taking clomiphene experienced lactation suppression, breast engorgement, discomfort, and decreased serum prolactin levels. For women on postpartum day 1, serum prolactin concentrations were significantly lower than baseline on day 3; for women on postpartum day 4, serum prolactin concentrations were significantly lower than baseline on day 5. No lactation suppression or decreased serum prolactin levels were observed in the placebo group.

[1]. Differential effects of isomers of clomiphene citrate on reproductive tissues in male mice. BJU Int. 2016 Feb;117(2):344-50.

[2]. Single-dose pharmacokinetics of clomiphene citrate in normal volunteers. Fertil Steril. 1986 Sep;46(3):392-6.

[3]. Sutherland RL. Estrogen antagonists in chick oviduct: antagonist activity of eight synthetic triphenylethylene derivatives and their interactions with cytoplasmic and nuclear estrogen receptors. Endocrinology. 1981 Dec;109(6):2061-8.

[4]. The biochemical and morphological response of hydrolytic enzymes in the developing brain to hypocholesterolemic agents. Acta Neuropathol. 1980;49(2):89-94.

[5]. Discovery of High-Affinity Ligands of σ1 Receptor, ERG2, and Emopamil Binding Protein by Pharmacophore Modeling and Virtual Screening. J Med Chem. 2005 Jul 28;48(15):4754-64.

Zucromifene is one of the geometric isomers of clomiphene citrate, a triphenylene derivative. Its anti-estrogenic activity in reproductive tissues affects male reproductive parameters, including testicular weight and sperm characteristics [1][3]. Clomiphene citrate may be carcinogenic and developmentally toxic, depending on state or federal labeling requirements. Zucromifene citrate is the cis isomer of clomiphene, which has weak estrogen agonist activity and has been evaluated for antitumor activity against breast cancer. (NCI04) Clomiphene citrate is the citrate form of clomiphene, a triphenylene nonsteroidal ovulation-inducing drug that has been evaluated for antitumor activity against breast cancer. Clomiphene has dual estrogenic and anti-estrogenic activity, competing with estrogen for binding to estrogen receptors in target tissues. The drug induces the pituitary gland to release gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH), leading to ovulation. (NCI04)
A triphenylstilbene derivative that can act as an estrogen agonist or antagonist, depending on the target tissue. Note that enclomiphene and zuclomiphene are the (E) and (Z) isomers of clomiphene, respectively.
See also: clomiphene citrate (note moved to).

C₃₂H₃₆CLNO₈

598.08

597.213

7619-53-6

Zuclomiphene-d4 citrate;2714316-71-7;Zuclomiphene-d5 citrate;1795132-80-7

3033832

White to off-white solid powder

5.314

4

9

14

42

708

0

CCN(CC)CCOC1=CC=C(C=C1)/C(=C(/C2=CC=CC=C2)\Cl)/C3=CC=CC=C3.C(C(=O)O)C(CC(=O)O)(C(=O)O)O

PYTMYKVIJXPNBD-OQKDUQJOSA-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-[(Z)-2-chloro-1,2-diphenylethenyl]phenoxy]-N,N-diethylethanamine;2-hydroxypropane-1,2,3-tricarboxylic acid

Zuclomiphene citrate; Zuclomiphene citrate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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 (~167.20 mM)

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.)