戈舍瑞林

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 戈舍瑞林
• 中文别名: 高舍瑞林；果丝瑞宁；性瑞林
• 英文名称: (2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-[(carbamoylamino)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-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]-2,3,3,4,4-pentadeuterio-5-oxopyrrolidine-2-carboxamide
• 化学式: C59H84N18O14
• 分子量: 1274.4
• InChiKey: BLCLNMBMMGCOAS-ORFGIKFDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.5
• 重原子数：
  91
• 可旋转键数：
  32
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.51
• 拓扑面积：
  496
• 氢给体数：
  17
• 氢受体数：
  16

ADMET

代谢

戈舍瑞林通过C端氨基酸的水解进行代谢，这是其主要清除机制。血清中主要循环成分似乎是1-7片段，而在一名健康男性志愿者的尿液中主要存在的成分是5-10片段。人类中戈舍瑞林的代谢产生了一组类似但范围较窄的代谢物，这些代谢物在其他物种中也有发现。在人类中发现的 所有代谢物在毒理学物种中也都有发现。

Metabolism of goserelin, by hydrolysis of the C-terminal amino acids, is the major clearance mechanism. The major circulating component in serum appeared to be 1-7 fragment, and the major component present in urine of one healthy male volunteer was 5-10 fragment. The metabolism of goserelin in humans yields a similar but narrow profile of metabolites to that found in other species. All metabolites found in humans have also been found in toxicology species.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

戈舍瑞林治疗期间，大约3%至5%的患者会出现轻度的血清酶水平升高，但超过正常上限3倍的情况非常罕见，报告的发生率不到1%。戈舍瑞林治疗期间的血清酶升高通常是短暂的且无症状的，即使在继续用药的情况下也会自行解决，很少需要调整剂量或停药。尽管戈舍瑞林已经使用了几十年，但仅有一例与临床明显的肝损伤相关，而且这一案例的关联性并不完全确凿。因此，不建议常规监测患者的肝功能测试异常。

Goserelin has been associated with mild serum enzyme elevations during therapy in 3% to 5% of patients, but values above 3 times the upper limit of normal are rare, being reported in less than 1% of recipients. The serum enzyme elevations during goserelin therapy have generally been transient and asymptomatic, resolving even with drug continuation and rarely requiring dose modification or discontinuation. Despite use for several decades, goserelin has been linked to only a single, and not entirely convincing, case of clinically apparent liver injury. Routine monitoring of patients for liver test abnormalities is not recommended.

来源:LiverTox

毒理性

• 解毒与急救

紧急和支援措施。保持呼吸道通畅，必要时协助呼吸。如果出现昏迷、癫痫、低血压和心律不齐，进行治疗。对于恶心和呕吐，使用甲氧氯普胺治疗，对于胃肠炎引起的液体丢失，使用静脉晶体液进行治疗。/抗肿瘤药物/

Emergency and supportive measures. Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, and arrhythmias if they occur. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. /Antineoplastic agents/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

骨髓抑制应由经验丰富的血液学家或肿瘤学家协助治疗。/抗肿瘤药物/

Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. /Antineoplastic agents/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

解毒。如果条件适当，口服活性炭。如果可以及时给予活性炭，小型到中等量的摄入后不需要进行洗胃。/抗肿瘤药物/

Decontamination. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. /Antineoplastic agents/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

增强消除。由于这些药物大多数迅速进入细胞内，透析和其他体外清除程序通常效果不佳。/抗肿瘤药物/

Enhanced elimination. Because of the rapid intracellular incorporation of most of these agents, dialysis and other extracorporeal removal procedures are generally not effective. /Antineoplastic agents/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

250微克戈舍瑞林水溶液皮下给药后，健康男性的表观分布容积为44.1 + 或 - 13.6升。戈舍瑞林的血浆蛋白结合率发现为27%。

The apparent volume of distribution determined after subcutaneous administration of 250 ug aqueous solution of goserelin was 44.1 + or - 13.6 liters for healthy males. The plasma protein binding of goserelin was found to be 27%.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

戈舍瑞林在注射Zoladex 10.8毫克长效剂给前列腺癌患者后的整体药代动力学特征已经确定。从长效剂中最初释放戈舍瑞林的速度相对较快，导致在给药后2小时达到峰值浓度。从第4天开始直到12周给药期结束，长效剂中戈舍瑞林的持续释放产生了相当稳定的系统性暴露。...在每隔12周注射四个长效剂后，没有临床上显著的戈舍瑞林积累。

The overall pharmacokinetic profile of goserelin following administration of a Zoladex 10.8 mg depot to patients with prostate cancer was determined. The initial release of goserelin from the depot was relatively rapid resulting in a peak concentration at 2 hours after dosing. From Day 4 until the end of the 12-week dosing interval, the sustained release of goserelin from the depot produced reasonably stable systemic exposure. ... There is no clinically significant accumulation of goserelin following administration of four depots administered at 12-week intervals.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

戈舍瑞林在健康男性和患者中的药代动力学已经确定。在健康男性中，将放射性标记的戈舍瑞林以单次250微克（水溶液）剂量通过皮下途径给药。放射性标记药物的吸收迅速，血药放射性水平峰值出现在给药后0.5到1.0小时之间。

The pharmacokinetics of goserelin have been determined in healthy male volunteers and patients. In healthy males, radiolabeled goserelin was administered as a single 250 ug (aqueous solution) dose by the subcutaneous route. The absorption of radiolabeled drug was rapid, and the peak blood radioactivity levels occurred between 0.5 and 1.0 hour after dosing.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在皮下注射戈舍瑞林放射性溶液后，戈舍瑞林的清除非常迅速，通过肝脏和尿液排泄的组合发生。超过90%的戈舍瑞林放射性溶液配方剂量通过尿液排出。在大约20%的尿液中回收的剂量是由未改变的戈舍瑞林组成。

Clearance of goserelin following subcutaneous administration of a radiolabeled solution of goserelin was very rapid and occurred via a combination of hepatic and urinary excretion. More than 90% of a subcutaneous radiolabeled solution formulation dose of goserelin was excreted in urine. Approximately 20% of the dose recovered in urine was accounted for by unchanged goserelin.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

戈舍瑞林是一种合成十肽类化合物，是黄体生成激素释放激素（LHRH）的类似物。出于实验目的，它被作为水溶液皮下注射，但用于治疗时，它被配制成能持续释放戈舍瑞林1（3.6毫克）或3（10.8毫克）个月的皮下储库。已经使用特定的放射免疫分析法生成了药物动力学数据。当作为溶液给药时，戈舍瑞林会迅速被吸收并从血清中消除，男性的平均消除半衰期（t1/2beta）为4.2小时，女性为2.3小时。给药储库后观察到的血清戈舍瑞林轮廓的主要形状由戈舍瑞林从可生物降解的乳酸-乙交酯共聚物基质中释放的速度决定，持续期为1或3个月。在多次给予这些储库时，没有临床相关性的戈舍瑞林积累。戈舍瑞林在排泄前被广泛代谢。其药物动力学不受肝功能损害的影响，但在严重肾功能损害的患者中，平均t1/2beta增加到12.1小时。这表明在肾功能损害的患者中，总肾清除率（肾代谢和未改变的药物）降低。当储库制剂给予老年患者或肾功能或肝功能受损的患者时，不需要调整剂量或给药间隔。...

Goserelin is a synthetic decapeptide analogue of luteinising hormone-releasing hormone (LHRH). For experimental purposes it has been administered subcutaneously as an aqueous solution, but for therapeutic use it is formulated as subcutaneous depots releasing goserelin over periods of 1 (3.6 mg) or 3 (10.8 mg) months. Pharmacokinetic data have been generated using a specific radioimmunoassay. When administered as a solution, goserelin is rapidly absorbed and eliminated from serum with a mean elimination half-life (t1/2beta) of 4.2 hours in males and 2.3 hours in females. The shapes of the observed serum goserelin profiles following administration of the depots are primarily determined by the rate of goserelin release from the biodegradable lactide-glycolide copolymer matrix over periods of 1 or 3 months. There is no clinically relevant accumulation of goserelin during multiple administration of these depots. Goserelin is extensively metabolized prior to excretion. Its pharmacokinetics are unaffected by hepatic impairment, but the mean t1/2beta increases to 12.1 hours in patients with severe renal impairment. This suggests that the total renal clearance (renal metabolism and unchanged drug) is decreased in patients with renal dysfunction. It is unnecessary to adjust the dose or administration interval when the depot formulations are administered to elderly patients or to those with impaired renal or hepatic function. ...

来源:Hazardous Substances Data Bank (HSDB)