10-(4-aminobutyl)-N-(1-amino-3-hydroxy-1-oxobutan-2-yl)-19-[(2-amino-3-naphthalen-2-ylpropanoyl)amino]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide

• 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
• 英文名称: 10-(4-aminobutyl)-N-(1-amino-3-hydroxy-1-oxobutan-2-yl)-19-[(2-amino-3-naphthalen-2-ylpropanoyl)amino]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide
• 化学式: C₅₄H₆₉N₁₁O₁₀S₂
• 分子量: 1096.3
• InChiKey: PUDHBTGHUJUUFI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  77
• 可旋转键数：
  17
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  406
• 氢给体数：
  13
• 氢受体数：
  14

ADMET

毒理性

• 肝毒性

在预注册的兰瑞肽研究中，血清酶水平没有显著变化，并且没有报告出现临床上明显的急性肝损伤。综合分析报告称，在治疗期间血清ALT、AST或碱性磷酸酶水平没有整体变化，也没有出现具有临床意义的升高。与其它生长抑素类似物一样，长期使用兰瑞肽治疗与胆泥和胆石症的高发生率相关，这可能是由于抑制胆囊收缩力和减少胆汁分泌所致。在长期研究中，20%到33%的使用兰瑞肽治疗的患者发生了胆石症。在某些情况下，会出现伴有轻至中度血清酶和胆红素升高的症状性胆管炎。然而，大多数与兰瑞肽相关的胆结石是无症状的。与奥曲肽不同，兰瑞肽和其他长效生长抑素类似物并未与临床上明显的肝损伤病例相关联，这种损伤独立于胆石症或胆泥之外，尽管它们的使用范围较窄，并未在许多使用奥曲肽治疗的情况中使用（如门脉高压、静脉曲张出血和患有先天性高胰岛素血症的婴儿）。

In preregistration studies of lanreotide, serum enzyme levels did not change appreciably and there were no reports of clinically apparent acute liver injury. Pooled analyses reported that there were no overall changes in serum ALT, AST or alkaline phosphatase levels during therapy or instances of clinically meaningful elevations with treatment. Prolonged therapy with lanreotide, as with other somatostatin analogues, was associated with a high rate of biliary sludge and cholelithiasis, probably due to inhibition of gall bladder contractility and decrease in bile secretion. In long term studies, cholelithiasis developed in 20% to 33% of lanreotide treated patients. In some instances, symptomatic cholecystitis occurred which can be accompanied by mild-to-moderate elevations in serum enzymes and bilirubin. However, most lanreotide associated gallstones were asymptomatic. Unlike octreotide, lanreotide and other long acting somatostatin analogues have not been liked to cases of clinically apparent liver injury, independent of cholelithiasis or biliary sludge, although they have had more limited use and have not been used in many of the clinical situations that were treated with octreotide (portal hypertension, variceal hemorrhage and infants with congenital hyperinsulinemia).

来源:LiverTox

毒理性

• 药物性肝损伤

醋酸兰瑞肽

Compound:lanreotide acetate

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI标注：模糊的DILI关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：2

Severity Grade:2

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

“标签部分：不良反应”

Label Section:Adverse reactions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

兰瑞肽在注射部位形成药物储库；因此，描述兰瑞肽吸收过程有两个阶段：1. 治疗初期几天内的快速皮下释放，其中未沉淀的药物被迅速吸收。2. 药物从储库中通过被动扩散缓慢释放。吸收与体重、性别和剂量无关。

Lanreotide forms a drug depot at the site of injection; therefore, there are 2 phases that describe the absorption of Lanreotide: 1. Initial rapid subcutaneous release during the first few days of treatment where drug that has not precipitated is rapidly absorbed. 2. Slow release of drug from the depot via passive diffusion. Absorption is independent of body weight, gender, and dosage.

来源:DrugBank

吸收、分配和排泄

• 消除途径

兰瑞肽的5%通过尿液排出，少于0.5%未改变地通过粪便排出，这表明胆汁排泄参与了其中。

<5% of lanreotide is excreted in urine, and less than 0.5% is excreted unchanged in the feces suggesting biliary excretion involvement.

来源:DrugBank

吸收、分配和排泄

• 分布容积

分布容积估计值 = 15.1 升

Estimated Volume of Distribution = 15.1 L

来源:DrugBank

吸收、分配和排泄

• 清除

预测清除率 = 23.1 升/小时

Estimated Clearance = 23.1 L/h

来源:DrugBank

反应信息

• 作为反应物：
  描述：

  DECAPEPTYL acetate 、 10-(4-aminobutyl)-N-(1-amino-3-hydroxy-1-oxobutan-2-yl)-19-[(2-amino-3-naphthalen-2-ylpropanoyl)amino]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide 以 水 为溶剂， 生成 Somatuline decapeptyl
  参考文献：
  名称：

  Sustained release drug formulations containing a carrier peptide

  摘要：

  本发明涉及一种给患者施用一种或多种治疗剂并在延长的时间内持续输送该药物或药物的方法，该方法包括：获取一种包括肽载体、一种或多种治疗剂和高达30％重量的药学上可接受、可溶、单体载体的制药组合物；通过注射将该制药组合物肌肉注射给患者，其中在与患者的体液相互作用后，该组合物自动形成凝胶，并在患者体内持续释放肽载体和药物或药物在延长的时间内。

  公开号：

  US07943575B2

文献信息

• [EN] PROCESS FOR PREPARATION OF LANREOTIDE ACETATE<br/>[FR] PROCÉDÉ DE PRÉPARATION D'ACÉTATE DE LANRÉOTIDE
  申请人：EMCURE PHARMACEUTICALS LTD

  公开号：WO2017178950A1

  公开（公告）日：2017-10-19

  Disclosed herein is an improved 4+4 solution phase synthesis of Lanreotide acetate. The process comprises coupling of two suitably protected tetrapeptide fragments which on deprotection, oxidation, followed by treatment with acetic acid provides Lanreotide acetate having desired purify.

  本文披露了一种改进的Lanreotide醋酸盐的4+4溶液相合成方案。该过程包括两个适当保护的四肽片段的偶联，经去保护、氧化处理，然后用乙酸处理得到具有所需纯度的Lanreotide醋酸盐。
• [EN] PROCESS FOR LANREOTIDE ACETATE PREPARATION<br/>[FR] PROCÉDÉ DE PRÉPARATION D'ACÉTATE DE LANRÉOTIDE
  申请人：EMCURE PHARMACEUTICALS LTD

  公开号：WO2017212390A1

  公开（公告）日：2017-12-14

  The invention relates to an improved method for 4+4 solution phase synthesis of Lanreotide acetate (1) comprising coupling of two suitably protected tetrapeptide fragments which on deprotection, oxidation, followed by treatment with acetic acid to provide Lanreotide acetate (1) having desired purity.

  本发明涉及一种改进的Lanreotide醋酸盐（1）的4+4溶液相合成方法，包括耦合两个适当保护的四肽片段，然后去保护、氧化，随后用乙酸处理以提供具有所需纯度的Lanreotide醋酸盐（1）。
• CONJUGATES OF SOMATOSTATIN ANALOGUES
  申请人：PROLYNX LLC

  公开号：US20160271227A1

  公开（公告）日：2016-09-22

  Conjugates of carriers and hydrogels for controlling the biological half-life of somatostatin and its analogs are disclosed.

  本发明揭示了用于控制生物半衰期的生物载体和水凝胶的共轭体，用于索马托斯汀及其类似物。
• Conjugates of somatostatin analogues
  申请人：ProLynx LLC

  公开号：US10413594B2

  公开（公告）日：2019-09-17

  Conjugates of carriers and hydrogels for controlling the biological half-life of somatostatin and its analogs are disclosed.

  本研究公开了用于控制体生长抑素及其类似物生物半衰期的载体和水凝胶共轭物。
• Liposomal anticancer compositions
  申请人：IriSys, LLC

  公开号：US11033520B2

  公开（公告）日：2021-06-15

  Provided herein includes methods and compositions for the treatment of cancer. Described herein are liposome encapsulated chemotherapeutic agents, encompassing a weakly basic anticancer compound and an acid or salt thereof, wherein the acid is oxalic acid or tartaric acid and methods for preparing and utilizing the same.

  本文提供了治疗癌症的方法和组合物。本文描述了脂质体包裹的化疗药物，包括弱碱性抗癌化合物和酸或其盐，其中酸为草酸或酒石酸，以及制备和使用这些药物的方法。