At 1000 ng/ml, ceterix diacetate inhibits the development of ES-2 cell lines. The antiproliferative effects of ceterprelix diacetate are similar to those of GnRH-I agonists, indicating that the GnRH-I system in cancer cells may not be subject to the GnRH-I agonists and antagonists dichotomy [2].

Absorption, Distribution and Excretion
Rapidly absorbed following subcutaneous injection. The mean absolute bioavailability following subcutaneous administration to healthy female subjects is 85%.
Following subcutaneous administration of 10 mg cetrorelix to males and females, only unchanged cetrorelix was detected in urine.
1.16 L/kg
1.28 ml/min·kg [adult healthy female with 3 mg single SC administration]
Following subcutaneous administration of 10 mg cetrorelix to males and females, only unchanged cetrorelix was detected in urine. In 24 hours, cetrorelix and small amounts of the (1-9), (1-7), (1-6), and (1-4) peptides were found in bile samples. 2-4% of the dose was eliminated in the urine as unchanged cetrorelix, while 5-10% was eliminated as cetrorelix and the four metabolites in bile. Therefore, only 7-14% of the total dose was recovered as unchanged cetrorelix and metabolites in urine and bile up to 24 hours. The remaining portion of the dose may not have been recovered since bile and urine were not collected for a longer period of time.
The volume of distribution of Cetrotide following a single intravenous dose of 3 mg is about 1 L/kg. In vitro protein binding to human plasma is 86%. Cetrotide concentrations in follicular fluid and plasma were similar on the day of oocyte pick-up in patients undergoing controlled ovarian stimulation. Following subcutaneous administration of Cetrotide 0.25 mg and 3 mg, plasma concentrations of cetrorelix were below or in the range of the lower limit of quantitation on the day of oocyte pick-up and embryo transfer.
Cetrotide is rapidly absorbed following subcutaneous injection, maximal plasma concentrations being achieved approximately one to two hours after administration. The mean absolute bioavailability of Cetrotide following subcutaneous administration to healthy female subjects is 85%.
Pharmacokinetic studies were performed predominantly in rats and dogs. Absorption from the sc injection site was rapid and complete and there were no differences in absorption with regard to sex or species. A linear relationship between dose and plasma AUC was evident. Distribution of cetrorelix was rapid. Main target organs were the kidney, liver, small intestine and organs containing the luteinising hormone releasing hormone (LHRH) receptor (pituitary gland, ovaries). Plasma protein binding amounted to 86%. Elimination from most tissues was rapid and occurred predominantly within 48 hr. ... Cetrorelix crosses the placenta only to a low extent. The distribution of cetrorelix or its metabolites into milk was not investigated. Cetrorelix is excreted unchanged into urine and after metabolism by peptidases into bile. ... Studies in healthy volunteers indicate that cetrorelix is excreted in a similar manner in humans, rats and dogs.
Following subcutaneous injection, the absolute bioavailability of cetrorelix was approximately 85% in both males and females. The apparent volume of distribution was 1.16 + or - 0.29 L/kg in females and 1.02 + or - 0.33 L/kg in males. The terminal half-life was about 10 hours after iv and 30 hours after subcutaneous injection with a trend towards lower values in female. Protein binding in human plasma was around 85%. Linear pharmacokinetics were observed following both single (0.25, 0.5 and 1.00 mg) and multiple dose administration (0.25 to 1.00 mg). The pharmacokinetics were linear up to a 3 mg dose.

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Metabolism / Metabolites
In in vitro studies, cetrorelix was stable against phase I- and phase II-metabolism. Cetrorelix was transformed by peptidases, and the (1-4) peptide was the predominant metabolite.
The main metabolite of cetrorelix in the rat bile was identified as being the heptapeptide (1-7). The metabolite was pharmacologically inactive in rats, in terms of testosterone suppression.
After subcutaneous administration of 10 mg Cetrotide to females and males, Cetrotide and small amounts of (1-9), (1-7), (1-6), and (1-4) peptides were found in bile samples over 24 hours. In in vitro studies, Cetrotide was stable against phase I- and phase II-metabolism. Cetrotide was transformed by peptidases, and the (1-4) peptide was the predominant metabolite.

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Biological Half-Life
~62.8 hours
In humans, the terminal half-life values after iv and sc administration were 8-9 hr and 24-40 hr, respectively.
The terminal half-lives in rats after iv and sc administration were 1-2 hr and 7-14 hr, respectively ... .
Elimination half life: Single 3 mg dose: 62.8 hr (38.2-108 hr); Single 0.25 mg dose: 5.0 hr (2.4-48.8 hr); 0.25 mg daily for 14 days: dose: 20.6 hr (4.1-179.3 hr) /From table/
Half-lives of greater than or equal to 100 hr were observed mainly in organs of elimination (liver, kidney), spleen and in the organs containing LHRH binding sites.

Protein Binding
86%

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Non-Human Toxicity Values
68.1 mg/kg was determined as the minimal lethal dose.

[1]. Characterization of gonadotropin-releasing hormone analogs based on a sensitive cellular luciferase reporter gene assay. Anal Biochem. 1997 Aug 15;251(1):17-23.

[2]. Role of gonadotropin-releasing hormone (GnRH) in ovarian cancer. Reprod Biol Endocrinol. 2003 Oct 7;1:65.

Therapeutic Uses
Cetrorelix is indicated for the inhibition of premature luteinizing hormone (LH) surges in women undergoing controlled ovarian stimulation.
/EXPL THER/ This randomized, placebo-controlled, single-blind, experimental study was performed on 45 Wistar adult female rats ... . After the peritoneal implantation of endometrial tissue, rats were randomized to three equal intervention groups: (i) control group, (ii) leuprolide group, and (iii) cetrorelix group. Six weeks later, following implant volume measurements (volume-1) by performing a second laparotomy, saline (0.1 mL/rat) was administered subcutaneously to the control group once a week, leuprolide (0.075 mg/kg) subcutaneously to the leuprolide group twice at 4-week intervals and cetrorelix (0.001 mg/rat/day) subcutaneously to the cetrorelix group for 8 weeks. At the end of the treatment, by performing a third laparotomy, implant volumes were remeasured (volume-2) and implants were totally excised for histopathological examination. The volume-1 and volume-2 values within the groups, and stromal and glandular tissue scores between the groups were compared. In both the leuprolide group and the cetrorelix group, volume-2 as compared to volume-1 had significantly reduced (P < 0.01, P < 0.01 respectively), while there was no significant volume change in the control group (P > 0.05). In this group, when compared with the control group, glandular and stromal tissues had significantly lessened (P < 0.01, P < 0.01 respectively). Leuprolide and cetrorelix were found to have similar efficacy in the regression of both the size and the histological structure of experimental endometriotic implants.

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Drug Warnings
Cetrorelix should be prescribed by health care providers who are experienced in fertility treatment. Before starting treatment with cetrorelix acetate, pregnancy must be excluded.
Elevations in liver function test results including ALT (SGPT), AST (SGOT), gamma-glutamyltransferase (GGT, gamma-glutamyl transpeptidase, GGTP), and alkaline phosphatase up to 3 times the upper limit of normal were reported in 1-2% of patients receiving cetrorelix during controlled ovarian stimulation.
Caution is advised in patients with hypersensitivity to GnRH. Carefully monitor these patients after the first injection. A severe anaphylactic reaction associated with cough, rash, and hypotension was observed in 1 patient after 7 months of treatment with 10 mg/day cetrorelix in a study for an indication unrelated to infertility.
Local site reactions (e.g. redness, erythema, bruising, itching, swelling and pruritus) were reported. Usually, they were of a transient nature, mild intensity and short duration.
For more Drug Warnings (Complete) data for CETRORELIX (8 total), please visit the HSDB record page.

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Pharmacodynamics
Cetrorelix is a synthetic decapeptide with gonadotropin-releasing hormone (GnRH) antagonistic activity. GnRH induces the production and release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the gonadotrophic cells of the anterior pituitary. Due to a positive estradiol (E2) feedback at midcycle, GnRH liberation is enhanced resulting in an LH-surge. This LH-surge induces the ovulation of the dominant follicle, resumption of oocyte meiosis and subsequently luteinization as indicated by rising progesterone levels. Cetrorelix competes with natural GnRH for binding to membrane receptors on pituitary cells and thus controls the release of LH and FSH in a dose-dependent manner.

C70H92CLN17O14.2(C2H4O2)

1429.669

130143-01-0

Cetrorelix Acetate;145672-81-7;Cetrorelix;120287-85-6

25074887

Typically exists as solid at room temperature

1.4±0.1 g/cm3

1768.4ºC at 760 mmHg

1023.3ºC

0mmHg at 25°C

1.668

2.69

16

16

38

102

2840

10

NC(NCCCCC(N1[C@H](C(N([C@H](C)C(N(C([C@H](N)CC2=CC=C(Cl)C=C2)=O)C([C@H](CC2=CC=C(OC(C)=O)C=C2)NC([C@H](COC(C)=O)NC([C@H](N)CC2=CN=CC=C2)=O)=O)=O)=O)C([C@H](NC(C)=O)CC2=CC3=CC=CC=C3C=C2)=O)=O)CCC1)=O)=N

SBNPWPIBESPSIF-MHWMIDJBSA-N

InChI=1S/C70H92ClN17O14/c1-39(2)31-52(61(94)82-51(15-9-28-77-69(73)74)68(101)88-30-10-16-58(88)67(100)79-40(3)59(72)92)83-60(93)50(14-8-29-78-70(75)102)81-63(96)54(34-43-20-25-49(91)26-21-43)86-66(99)57(38-89)87-65(98)56(36-45-11-7-27-76-37-45)85-64(97)55(33-42-18-23-48(71)24-19-42)84-62(95)53(80-41(4)90)35-44-17-22-46-12-5-6-13-47(46)32-44/h5-7,11-13,17-27,32,37,39-40,50-58,89,91H,8-10,14-16,28-31,33-36,38H2,1-4H3,(H2,72,92)(H,79,100)(H,80,90)(H,81,96)(H,82,94)(H,83,93)(H,84,95)(H,85,97)(H,86,99)(H,87,98)(H4,73,74,77)(H3,75,78,102)/t40-,50-,51+,52+,53-,54+,55-,56-,57+,58+/m1/s1

(2S)-1-[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-5-(carbamoylamino)pentanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]-N-[(2R)-1-amino-1-oxopropan-2-yl]pyrrolidine-2-carboxamide

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.)