In isolated rat hypothalamic-neurohypophyseal explants, histrelin (10–100 nM) promotes the release of vasopressin (VP) [4]. In the rat hypothalamic-neurohypophyseal system, histrelin (100 nM) promotes the production of oxytocin (OT) [5].

In Csfmop/Csfmop mice, histrelin (0.1 mg/kg, subcutaneous injection) raises circulating LH concentrations [2]. Rabbit kidneys with subcutaneous injections of histrelin (10, 30, or 100 μg/day) have less intimal glands.

Animal/Disease Models: Csfmop/Csfmop mice [2]
Doses: 0.001, 0.05, and 0.1 mg/kg
Route of Administration: Results of subcutaneous injection: serum FSH concentration increased 4-fold.

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Animal/Disease Models: Rabbit [3]
Doses: 10, 30 or 100 μg/day
Route of Administration: subcutaneous injection for 4 weeks
Experimental Results: Caused endometrial glandular degeneration and stroma thinning.

Absorption, Distribution and Excretion
Advanced prostate cancer patients (n = 17) that received a subcutaneous histrelin implant (Vantas, Endo Pharmaceuticals) had peak serum concentrations of 1.10 ± 0.375 ng/mL (mean ± SD) at 12 hours. The continuous subcutaneous release of the histrelin implant was confirmed, as serum levels were sustained throughout the 52-week dosing period. At the end of the 52-week period, the mean serum histrelin concentration was 0.13 ± 0.065 ng/mL. In patients that received a second implant at the end of the 52-week period, the serum histrelin concentration in the first eight weeks was similar to the one detected with the first implant. On average, the residual drug content of 41 histrelin implants (Vantas, Endo Pharmaceuticals) was 56.7 ± 7.71 mcg/day over 52 weeks. Compared to healthy male volunteers that received a subcutaneous bolus dose, the relative bioavailability of histrelin in patients with prostate cancer and normal renal and hepatic function was 92%. In children with central precocious puberty (CPP, n=47) that received a subcutaneous histrelin implant (Supprelin LA, Endo Pharmaceuticals), the median maximum serum histrelin concentration over the study period was 0.43 ng/mL, which is expected to maintain gonadotropins at prepubertal levels. There were no pharmacokinetic differences between patients previously treated with luteinizing hormone-releasing hormone (LHRH) agonists and those that had not. Food-drug interaction studies have not been performed for histrelin products. Serum histrelin concentrations are 50% higher in prostate cancer patients with mild to severe renal impairment compared to those with no renal or hepatic impairment; however, this difference is not considered clinically relevant.
Drug excretion studies have not been performed for histrelin.
The apparent volume of distribution of histrelin following a subcutaneous bolus dose of histrelin (Vantas, Endo Pharmaceuticals, 500 mcg) in healthy volunteers was 58.4 ± 7.86 L.
In prostate cancer patients (n=17) administered a histrelin implant (Vantas, Endo Pharmaceuticals) the apparent clearance was 174 ± 56.5 mL/min (mean ± SD).
Histrelin acetate is not active when given orally.
Following subcutaneous insertion of a histrelin acetate implant in patients with advanced prostate cancer, peak serum concentrations of histrelin occurred at a median of 12 hours; the drug is delivered continuously at a rate of 50-60 ug daily over 12 months.
Following subcutaneous insertion of one Vantas (histrelin implant) 50 mg implant in advanced prostate cancer patients (n = 17), peak serum concentrations of 1.10 +/- 0.375 ng/mL (mean +/- SD) occurred at a median of 12 hours.
The average rate of subcutaneous drug release from 41 implants assayed for residual drug content was 56.7 +/- 7.71 ug/day over the 52 week dosing period.
For more Absorption, Distribution and Excretion (Complete) data for HISTRELIN (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
As a synthetic peptide, histrelin is expected to be metabolized by proteases throughout the body. This will likely result in several peptide fragments produced by hydrolysis. In an _in vitro_ drug metabolism study using human hepatocytes, a single histrelin metabolite resulting from C-terminal dealkylation was identified.
An in vitro drug metabolism study using human hepatocytes identified a single histrelin metabolite resulting from C-terminal dealkylation. Peptide fragments resulting from hydrolysis are also likely metabolites.

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Biological Half-Life
In healthy volunteers administered a subcutaneous bolus dose of histrelin, the terminal half-life was 3.92 ± 1.01 hr (mean ± SD).
The mean terminal half-life of the drug following subcutaneous injection of a single 500-ug dose was approximately 3.92 hours in healthy men.

Hepatotoxicity
Histrelin has been associated with serum enzyme elevations during therapy in rates similar to those of other GnRH analogues. The serum enzyme elevations are generally mild, asymptomatic and resolve even without dose adjustment or drug discontinuation. ALT elevations above 3 times the upper limit of normal occur in less than 1% of recipients. Histrelin has been linked to a single case of acute liver injury, but it was unclear from the report whether the episode was associated with jaundice or symptoms and other diagnoses remained possible. Thus, clinically apparent liver injury from histrelin may occur, but it is extremely rare and usually self-limited in course. There have been no episodes of acute liver failure, chronic hepatitis or vanishing bile duct syndrome associated with histrelin or other GnRH analogue therapy.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).

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Protein Binding
In an _in vitro_ measurement, the fraction of histrelin (Vantas, Endo Pharmaceuticals) unbound in plasma was 29.5% ± 8.9% (mean ± SD).

[1]. Histrelin: in advanced prostate cancer. Drugs. 2010 Mar 26;70(5):623-30.

[2]. Colony-stimulating factor-1 plays a major role in the development of reproductive function in male mice. Mol Endocrinol. 1997 Oct;11(11):1636-50.

[3]. Development of an animal model for quantitatively evaluating effects of drugs on endometriosis. Fertil Steril. 1985 Sep;44(3):410-5.

[4]. Vasopressin release from the rat hypothalamo-neurohypophysial system: effects of gonadotrophin-releasing hormone (GnRH), its analogues and melatonin. J Physiol Pharmacol. 2010 Aug;61(4):459-66.

[5]. Hypothalamic gonadotropin-releasing hormone receptor activation stimulates oxytocin release from the rat hypothalamo-neurohypophysial system while melatonin inhibits this process. Brain Res Bull. 2010 Jan 15;81(1):185-90.

Therapeutic Uses
Gonadotropin-Releasing Hormone agonist
/Histrelin/ is indicated in the palliative treatment of advanced prostate cancer. /Included in US product label/
/Histrelin/ is a gonadotropin releasing hormone (GnRH) agonist indicated for the treatment of children with central precocious puberty (CPP). /Included in US product label/

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Drug Warnings
/Histrelin is contraindicated in patients with/ known hypersensitivity to histrelin or any ingredient in the formulation, other gonadotropin-releasing hormone (GnRH) agonists, or GnRH.
Like other GnRH agonists, histrelin causes a transient increase in serum testosterone concentrations during the first week of treatment. Worsening of signs and/or symptoms of prostate cancer and/or development of new manifestations (e.g., bone pain, neuropathy, hematuria, ureteral or bladder outlet obstruction) may occur during the first few weeks of therapy.
Cases of ureteral obstruction and spinal cord compression, which may contribute to paralysis with or without fatal complications, have been reported with GnRH agonists. Patients with metastatic vertebral lesions and/or urinary tract obstruction should be closely observed during the first few weeks of therapy. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted.
Anaphylactic reactions have been reported with synthetic gonadotropin-releasing hormone (GnRH) or GnRH agonists.
For more Drug Warnings (Complete) data for HISTRELIN (16 total), please visit the HSDB record page.

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Pharmacodynamics
Histrelin inhibits gonadotropin secretion through the reversible down-regulation of gonadotropin-releasing hormone (GnRH) receptors in the pituitary gland and desensitization of the pituitary gonadotropes. In pediatric patients with central precocious puberty (CPP), long-term treatment with histrelin acetate suppresses the luteinizing hormone (LH) response to GnRH, causing LH levels to decrease to prepubertal levels within one month of treatment. This reduces ovarian and testicular steroidogenesis and slows down linear growth velocity, improving the chance of attaining predicted adult height. When given orally, histrelin acetate is not active. Both histrelin products (Vantas and Supprelin LA from Endo Pharmaceuticals) cause a transient increase in serum concentrations of estradiol in females and testosterone in both sexes during the first week of treatment. Laboratory tests are also recommended in order to monitor hormone levels. For pediatric patients with central precocious puberty (CPP) using histrelin (Supprelin LA, Endo Pharmaceuticals), LH, follicle-stimulating hormone and estradiol or testosterone should be monitored. In patients with advanced prostate cancer using histrelin (Vantas, Endo Pharmaceuticals), testosterone and prostate-specific antigen should be measured periodically. Issues such as breakage during insertion and difficulty locating and removing implants have been reported. The Supprelin LA (Endo Pharmaceuticals) product label alerts users about psychiatric events, convulsions and cases of pseudotumor cerebri (idiopathic intracranial hypertension) that have been reported in patients receiving GnRH agonists. The Vantas (Endo Pharmaceuticals) product label alerts users about cases of spinal cord compression and urinary tract obstruction, and an increased risk of hyperglycemia/diabetes and cardiovascular disease in men receiving GnRH agonists.

C66H86N18O12

1323.50244

1322.667

76712-82-8

Histrelin acetate;220810-26-4

25077993

White to off-white solid powder

1.5±0.1 g/cm3

1800.6ºC at 760 mmHg

1042.8ºC

1.701

0.09

15

15

34

96

2660

9

CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC2=CN(C=N2)CC3=CC=CC=C3)NC(=O)[C@H](CC4=CC=C(C=C4)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC5=CNC6=CC=CC=C65)NC(=O)[C@H](CC7=CN=CN7)NC(=O)[C@@H]8CCC(=O)N8

HHXHVIJIIXKSOE-QILQGKCVSA-N

InChI=1S/C66H86N18O12/c1-4-70-64(95)55-17-11-25-84(55)65(96)48(16-10-24-71-66(67)68)76-58(89)49(26-38(2)3)77-62(93)53(30-43-34-83(37-74-43)33-40-12-6-5-7-13-40)81-59(90)50(27-39-18-20-44(86)21-19-39)78-63(94)54(35-85)82-60(91)51(28-41-31-72-46-15-9-8-14-45(41)46)79-61(92)52(29-42-32-69-36-73-42)80-57(88)47-22-23-56(87)75-47/h5-9,12-15,18-21,31-32,34,36-38,47-55,72,85-86H,4,10-11,16-17,22-30,33,35H2,1-3H3,(H,69,73)(H,70,95)(H,75,87)(H,76,89)(H,77,93)(H,78,94)(H,79,92)(H,80,88)(H,81,90)(H,82,91)(H4,67,68,71)/t47-,48-,49-,50-,51-,52-,53+,54-,55-/m0/s1

(2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-3-(1-benzylimidazol-4-yl)-1-[[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-[(2S)-2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]-5-oxopyrrolidine-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.)