GnRHR

地加瑞克仅表现出非常弱的组胺释放特性，并且在 LHRH 拮抗剂（包括 Cetrorelix 、 Abarelix 和 Ganirelix ）中组胺释放能力最低 [1]。 Degarelix（1 nM-10 μM，0-72 小时）可降低所有前列腺细胞系（WPE1-NA22、WPMY-1、BPH-1、VCaP 细胞）的细胞活力，PC-3 细胞除外[2] 。 Degarelix（10 μM，0-72 小时）通过细胞凋亡对前列腺细胞生长产生直接影响[2]。细胞活力测定[2] 细胞系：WPMY-1、WPE1-NA22、BPH-1、LNCaP 和 VCaP 浓度：1 nM-10 μM 孵育时间：WPMY-1 细胞 48 小时和 72 小时，WPE1-NA22 细胞 72 小时、BPH-1 细胞（48 小时和 72 小时）、LNCaP 细胞（48 小时和 72 小时） 结果：除 PC-3 细胞外，所有前列腺细胞系的细胞活力均降低。细胞凋亡分析[2] 细胞系：WPE1-NA22、BPH-1、LNCaP 和 VCaP 浓度：10 μM 孵育时间：24、48 和 72 小时 结果：诱导 caspase 3/7 激活显着增加。

地加瑞克（0-10 μg/kg；皮下注射；一次）以剂量依赖性方式降低去势大鼠血浆 LH 水平和血浆睾酮水平[3]。当在微粒体和来自动物肝组织的冷冻保存的肝细胞中孵育时，地加瑞克是稳定的。在大鼠和狗中，大部分地加瑞克剂量在 48 小时内通过尿液和粪便以等量（每种基质中 40-50%）消除，而在猴子中，主要排泄途径是粪便（50%）和肾脏（22 %)[4]。动物模型：雄性 Sprague-Dawley 大鼠，去势[3] 剂量：0.3、1、3 和 10 μg/kg 或 12.5、50 和 200 μg/kg 给药方法：皮下注射，一次 结果：产生剂量依赖性且可逆的最小有效剂量为 3 μg/kg 即可降低血浆 LH 水平。对于50μg/kg和200μg/kg剂量，吸收t1/2值为4分钟和30分钟，Tmax值为1小时和5小时，表观血浆消失t1/2值为12小时和67小时，分别。最小有效剂量为 1 μg/kg，血浆睾酮水平呈剂量依赖性下降。

Male Sprague-Dawley rats, castrated
0.3, 1, 3 and 10 μg/kg or 12.5, 50, and 200 μg/kg
Subcutaneous injection, once

Absorption, Distribution and Excretion
Degarelix forms a depot at the site of injection after subcutaneous administration from which the drug slowly released into circulation. After a single bolus dose of 2mg/kg, peak plasma concentrations of degarelix occured within 6 hours at a concentration of 330 ng/mL. Ki = 0.082 ng/mL and 93% of receptors were fully suppressed; MRT = 4.5 days.
Fecal (70% to 80%) and renal (20%-30% of unchanged drug)
Central compartment: 8.88 - 11.4 L; Peripheral compartment: 40.9 L
Following subcutaneous administration of degarelix to prostate cancer patients the clearance is approximately 9 L/hr.
The protein binding in plasma of mouse, rat, dog, monkey, and humans was measured using the (3)H-degarelix and the ultracentrifugation technique. The plasma binding was approximately 90% in animals and humans. Distribution of radioactivity following administration of (3)H-degarelix was studied in rats, dogs and monkeys, doses were respectively 0.03 mg/kg, 0.003 mg/kg and 0.0082 mg/kg. Radioactivity of tissues was measured after sacrifice and necropsy of the animals. High concentrations were mainly seen at the s.c. injection site and in organs of excretion. Lower concentrations, but still higher than those in plasma were generally seen in some organs of the endocrine and reproductive systems most of which contain specific receptors for LHRH, and organs rich in reticuloendothelial cells during the elimination phase. There was no indication of tissue retention.
Balance of the radioactivity following SC administration of (3)H-degarelix was studied in rats, dogs and monkeys. Degarelix was mainly excreted unchanged via the urine and was subject to sequential peptidic degradation during its elimination via the hepato-biliary pathway in both animals and man.
After subcutaneous administration, degarelix forms a local depot at the injection site, leading to retarded and extended release of the active drug. The release from the depot is dependent on the concentration in the dose formulation and the dose volume. Furthermore, in repeat dose studies, increasing concentrations in the dose formulation resulted in sub-proportional increases in maximum plasma concentration (Cmax) and area under plasma concentration vs time in the dosing interval (AUC), an increase in trough plasma concentration (Ctrough), an increase in terminal half-life (t1/2), thus increasing the time to reach steady state, and a tendency of increase in time to maximum plasma concentration (Tmax).
Degarelix forms a depot at the injection site following subcutaneous administration from which the drug is very slowly released into circulation. Peak plasma concentrations of degarelix generally occur within 2 days following subcutaneous administration of a single 240 mg dose at a concentration of 40 mg/mL.. The pharmacokinetic behavior of degarelix is strongly influenced by its concentration in the injection solution. Approximately 90% of the drug is bound to plasma proteins. No quantitatively substantial metabolites have been detected in plasma following subcutaneous adminstration. Degarelix does not appear to be a substrate, inducer, or inhibitor of the cytochrome P-450 (CYP) enzyme or P-glycoprotein transport systems based on in vitro studies. Degarelix is eliminated in a biphasic manner, with a median terminal half-life of about 53 days following subcutaneous administration of a 240 mg dose at a concentration of 40 mg/mL in prostate cancer patients. Degarelix is subject to peptide hydrolysis during its passage through the hepatobiliary system and is mainly excreted as peptide fragments in feces. Approximately 20-30% of a given dose of degarelix is renally eliminated, suggesting that approximately 70-80% is excreted via the hepatobiliary system.
For more Absorption, Distribution and Excretion (Complete) data for Degarelix (6 total), please visit the HSDB record page.

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Metabolism / Metabolites
70% - 80% of degarelix is subject to peptide hydrolysis during its passage through the hepatobiliary system and then fecally eliminated. No active or inactive metabolites or involvement of CYP450 isozymes.
The stability of degarelix was studied in liver microsomes from males in rat, guinea pig, rabbit, dog, monkey, and human, for up to 60 min. No degradation of degarelix was detected in liver microsomes from rabbit, dog, monkey, and human. Tendency to minor degradation of degarelix was seen in liver microsomes from guinea pig and rat. The in vitro metabolism of degarelix was further investigated in human liver microsomes for up to 60 min. The metabolism pattern of degarelix was reported to be similar in humans and animals. Degarelix was virtually no substrate for oxidative metabolism, but was degraded by peptidases with generation of various truncated peptides. Only low concentration of one metabolite was seen in human plasma, and this metabolite was also seen in rats, dogs and monkeys.

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Biological Half-Life
Terminal half-life: 41.5 - 70.2 days; Absorption half-life: 32.9 hours; Half-life from injection site: 1.17 days.
Degarelix is eliminated in a biphasic manner, with a median terminal half-life of about 53 days following subcutaneous administration of a 240 mg dose at a concentration of 40 mg/mL in prostate cancer patients.

Hepatotoxicity
Degarelix therapy has been associated with serum enzyme elevations in up to one-third of patients. The elevations, however, are generally mild and self-limited, resolving even without dose adjustment. ALT values above 3 times the ULN occur in less than 1% of patients. Occasional patients require drug discontinuation because of serum enzyme elevations, but no instances of liver injury with jaundice or clinically apparent acute liver injury were reported in the initial clinical trials of degarelix. Since its approval and more widescale use, there have been no published reports of clinically apparent liver injury attributed to degarelix, although its general use has been limited.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Protein Binding
90% of the drug is bound to plasma proteins.

[1]. An update on the use of degarelix in the treatment of advanced hormone-dependent prostate cancer. Onco Targets Ther. 2013 Apr 16;6:391-402.

[2]. In search of the molecular mechanisms mediating the inhibitory effect of the GnRH antagonistdegarelix on human prostate cell growth. PLoS One. 2015 Mar 26;10(3):e0120670.

[3]. Pharmacological profile of a new, potent, and long-acting gonadotropin-releasing hormoneantagonist: degarelix. J Pharmacol Exp Ther. 2002 Apr;301(1):95-102.

[4]. Metabolite profiles of degarelix, a new gonadotropin-releasing hormone receptor antagonist, in rat, dog, and monkey. Drug Metab Dispos. 2011 Oct;39(10):1895-903.

Degarelix is a polypeptide.
Degarelix is used for the treatment of advanced prostate cancer. Degarelix is a synthetic peptide derivative drug which binds to gonadotropin-releasing hormone (GnRH) receptors in the pituitary gland and blocks interaction with GnRH. This antagonism reduces luteinising hormone (LH) and follicle-stimulating hormone (FSH) which ultimately causes testosterone suppression. Reduction in testosterone is important in treating men with advanced prostate cancer. Chemically, it is a synthetic linear decapeptide amide with seven unnatural amino acids, five of which are D-amino acids. FDA approved on December 24, 2008.
Degarelix is a Gonadotropin Releasing Hormone Receptor Antagonist. The mechanism of action of degarelix is as a Gonadotropin Releasing Hormone Receptor Antagonist. The physiologic effect of degarelix is by means of Decreased GnRH Secretion.
Degarelix is a parenterally administered, gonadotropin releasing hormone (GnRH) antagonist that effectively blocks androgen production and is used to treat advanced prostate cancer. Degarelix therapy is associated with serum enzyme elevations during therapy, but has yet to be linked to instances of clinically apparent acute liver injury.
Degarelix is a long-acting, synthetic peptide with gonadotrophin-releasing hormone (GnRH) antagonistic properties. Degarelix targets and blocks GnRH receptors located on the surfaces of gonadotroph cells in the anterior pituitary, thereby reducing secretion of luteinizing hormone (LH) by pituitary gonadotroph cells and so decreasing testosterone production by interstitial (Leydig) cells in the testes.
See also: Degarelix Acetate (has salt form).

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Drug Indication
In Canada and the US, degarelix is indicated for the treatment of advanced prostate cancer in patients requiring androgen deprivation therapy. In the EU, it is more specifically indicated for the treatment of adult male patients with advanced hormone-dependent prostate cancer, and for treatment of high-risk localized and locally advanced hormone-dependent prostate cancer, in combination with radiotherapy or as a neo-adjuvant prior to radiotherapy.
FDA Label
Degarelix Accord is a gonadotrophin releasing hormone (GnRH) antagonist indicated: for treatment of adult male patients with advanced hormone-dependent prostate cancer . for treatment of high-risk localised and locally advanced hormone dependent prostate cancer in combination with radiotherapy. as neo-adjuvant treatment prior to radiotherapy in patients with high-risk localised or locally advanced hormone dependent prostate cancer .
FIRMAGON is a gonadotrophin releasing hormone (GnRH) antagonist indicated: - for treatment of adult male patients with advanced hormone-dependent prostate cancer . - for treatment of high-risk localised and locally advanced hormone dependent prostate cancer in combination with radiotherapy. - as neo-adjuvant treatment prior to radiotherapy in patients with high-risk localised or locally advanced hormone dependent prostate cancer .

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Mechanism of Action
Degarelix competitively inhibits GnRH receptors in the pituitary gland, preventing the release of luteinizing hormone (LH) and follicle stimulating hormone. Reduced LH suppresses testosterone release, which slows the growth and reduces the size of prostate cancers.
Degarelix is a selective gonadotrophin releasing-hormone (GnRH) antagonist that competitively and reversibly binds to the pituitary GnRH receptors, thereby rapidly reducing the release of the gonadotrophins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), and thereby reducing the secretion of testosterone (T) by the testes. Prostatic carcinoma is known to be androgen sensitive and responds to treatment that removes the source of androgen. Unlike GnRH agonists, GnRH antagonists do not induce a LH surge with subsequent testosterone surge/tumour stimulation and potential symptomatic flare after the initiation of treatment.
Degarelix, a synthetic decapeptide, is a gonadotropin-releasing hormone (GnRH, luteinizing hormone-releasing hormone, gonadorelin) antagonist. The drug immediately, competitively, and reversibly binds to and blocks GnRH receptors in the pituitary, thereby reducing the release of gonadotropins (i.e., luteinizing hormone [LH], follicle stimulating hormone [FSH]) and, consequently, testosterone without initial stimulation of the hypothalamic-pituitary-gonadal axis and the associated testosterone surge. Degarelix appears to have low histamine-releasing potential compared with other GnRH antagonists; there have been no signs of immediate- or late-onset systemic allergic reactions with degarelix.

C₈₂H₁₀₃CLN₁₈O₁₆

1632.26

1630.748

C, 60.34; H, 6.36; Cl, 2.17; N, 15.45; O, 15.68

214766-78-6

Degarelix-d7; Degarelix acetate hydrate; 934246-14-7;214766-78-6;Degarelix-d7;934016-19-0

16136245

White to off-white solid powder

1.3±0.1 g/cm3

1.620

4.45

512.87

17

18

41

117

3390

11

C[C@H](C(N)=O)NC([C@H]1N(C([C@H](CCCCNC(C)C)NC([C@H](CC(C)C)NC([C@@H](CC2=CC=C(NC(N)=O)C=C2)NC([C@H](CC3=CC=C(NC([C@H](CC(N4)=O)NC4=O)=O)C=C3)NC([C@H](CO)NC([C@@H](CC5=CC=CN=C5)NC([C@@H](CC6=CC=C(Cl)C=C6)NC([C@@H](CC7=CC=C8C=CC=CC8=C7)NC(C)=O)=O)=O)=O)=O)=O)=O)=O)=O)CCC1)=O

MEUCPCLKGZSHTA-XYAYPHGZSA-N

InChI=1S/C82H103ClN18O16/c1-45(2)35-60(72(107)92-59(16-9-10-33-87-46(3)4)80(115)101-34-12-17-68(101)79(114)88-47(5)70(84)105)93-74(109)63(38-51-23-30-58(31-24-51)91-81(85)116)95-76(111)64(39-50-21-28-57(29-22-50)90-71(106)66-42-69(104)100-82(117)99-66)97-78(113)67(44-102)98-77(112)65(41-53-13-11-32-86-43-53)96-75(110)62(37-49-19-26-56(83)27-20-49)94-73(108)61(89-48(6)103)40-52-18-25-54-14-7-8-15-55(54)36-52/h7-8,11,13-15,18-32,36,43,45-47,59-68,87,102H,9-10,12,16-17,33-35,37-42,44H2,1-6H3,(H2,84,105)(H,88,114)(H,89,103)(H,90,106)(H,92,107)(H,93,109)(H,94,108)(H,95,111)(H,96,110)(H,97,113)(H,98,112)(H3,85,91,116)(H2,99,100,104,117)/t47-,59+,60+,61-,62-,63-,64+,65-,66+,67+,68+/m1/s1

(4S)-N-[4-[(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-[[(2R)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-[[(2R)-1-amino-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxo-6-(propan-2-ylamino)hexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[4-(carbamoylamino)phenyl]-1-oxopropan-2-yl]amino]-3-oxopropyl]phenyl]-2,6-dioxo-1,3-diazinane-4-carboxamide

Degarelix Free Base; HSDB 7817; HSDB7817; HSDB-7817

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: ~10 mg/mL (~6.1 mM)
H2O: ~5 mg/mL (~3.1 mM)

配方 1 中的溶解度: ≥ 1 mg/mL (0.61 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 10.0 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 1 mg/mL (0.61 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 10.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 1 mg/mL (0.61 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 10.0 mg/mL 澄清 DMSO 储备液加入900 μL 玉米油中，混合均匀。

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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。