18-[[(1R)-4-[2-[2-[2-[2-[2-[2-[[(5S)-5-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-[[2-[[(2S)-2-[[2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]-2-methylpropanoyl]amino]-4-carboxybutanoyl]amino]acetyl]amino]-3-hydroxybutanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-4-carboxybutanoyl]amino]acetyl]amino]-5-oxopentanoyl]amino]propanoyl]amino]propanoyl]amino]-6-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-carbamimidamido-1-[[2-[[(2S)-5-carbamimidamido-1-(carboxymethylamino)-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-6-oxohexyl]amino]-2-oxoethoxy]ethoxy]ethylamino]-2-oxoethoxy]ethoxy]ethylamino]-1-carboxy-4-oxobutyl]amino]-18-oxooctadecanoic acid

• 分子结构分类: 有机化合物 - 有机聚合物 - 多肽
• 英文名称: 18-[[(1R)-4-[2-[2-[2-[2-[2-[2-[[(5S)-5-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-[[2-[[(2S)-2-[[2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]-2-methylpropanoyl]amino]-4-carboxybutanoyl]amino]acetyl]amino]-3-hydroxybutanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-4-carboxybutanoyl]amino]acetyl]amino]-5-oxopentanoyl]amino]propanoyl]amino]propanoyl]amino]-6-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-carbamimidamido-1-[[2-[[(2S)-5-carbamimidamido-1-(carboxymethylamino)-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-6-oxohexyl]amino]-2-oxoethoxy]ethoxy]ethylamino]-2-oxoethoxy]ethoxy]ethylamino]-1-carboxy-4-oxobutyl]amino]-18-oxooctadecanoic acid
• 化学式: C₁₈₇H₂₉₁N₄₅O₅₉
• 分子量: 4114.0
• InChiKey: DLSWIYLPEUIQAV-CCUURXOWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -5.8
• 重原子数：
  291
• 可旋转键数：
  151
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  1650
• 氢给体数：
  57
• 氢受体数：
  63

ADMET

代谢

Semaglutide 在肽骨架上被裂解，随后是脂肪酸链的β-氧化。天然存在的GLP-1迅速被二肽基肽酶-4（DPP-4）和其他普遍存在于人体组织中的酶代谢。化学结构修饰使得semaglutide对胃肠道DPP-4酶的降解作用不太敏感。它被缓慢且广泛地代谢，大约83%的给药剂量在血浆中以未改变的药物形式被测量到。神经内肽酶（NEP）是另一种代谢这种药物的酶。DPP-4使semaglutide失活，截断N端片段，而NEP水解肽键。在人类血浆中已经鉴定出semaglutide的六种不同代谢物。主要代谢物P3约占摄入剂量的7.7%。

Semaglutide is cleaved at the peptide backbone, followed by β‐oxidation of the fatty acid chain. Naturally occurring GLP‐1 is quickly metabolized by dipeptidyl peptidase‐4 (DPP‐4) and other enzymes, which is ubiquitous in human tissues. Chemical structure modifications render semaglutide less susceptible to enzymatic degradation by gastrointestinal DPP‐4 enzymes. It is slowly and extensively metabolized, with about 83% of the administered dose measured in the plasma as unchanged drug. Neural endopeptidase (NEP) is another enzyme that metabolizes this drug. DPP-4 inactivates semaglutide, truncating the N-terminal segment while NEP hydrolyzes peptide bondsSix different metabolites of semaglutide have been identified in human plasma. The major metabolite, named P3, accounts for about 7.7% of an ingested dose.

来源:DrugBank

毒理性

• 肝毒性

在大规模临床试验中，与安慰剂或比较剂相比，司美格鲁肽治疗的血清酶升高并不常见，也没有报告出现临床上明显的肝损伤。实际上，司美格鲁肽和其他GLP-1类似物的治疗通常与血清转氨酶水平（和肝脂肪变性）的改善相关，使它们可能成为非酒精性脂肪肝的治疗方法。自从获得许可以来，没有发表过由于司美格鲁肽导致肝毒性的案例报告，产品标签也没有将肝损伤列为不良事件。因此，如果司美格鲁肽确实导致肝损伤，这种情况也一定非常罕见。

In large clinical trials, serum enzyme elevations were no more common with semaglutide therapy than with placebo or comparator agents, and no instances of clinically apparent liver injury were reported. Indeed, treatment with semaglutide and other GLP-1 analogues is often associated with improvements in serum aminotransferase levels (and hepatic steatosis) making them possible treatments for nonalcoholic fatty liver. Since licensure, there have been no published case reports of hepatotoxicity due to semaglutide and the product label does not list liver injury as an adverse event. Thus, liver injury due to semaglutide must be rare, if it occurs at all.

来源:LiverTox

毒理性

• 毒性总结

**过量** 单次摄入高达4毫克的过量报告中有出现。恶心是最常见的症状。在临床试验中报告过量的所有患者都已完全恢复。应根据患者的状况给予适当的支持性治疗。由于这种药物的半衰期约为1周，可能需要长时间的观察和治疗。对于semaglutide过量，没有解毒剂。

The oral LD50 of semaglutide is 270 mg/kg in the rat. **Overdose** Overdoses of up to 4mg in one ingestion have been reported. Nausea was the most commonly reported symptom. All patients in clinical trials that reported an overdose recovered fully. Appropriate supportive care should be given according and dictated by the patient's condition. Prolonged observation and treatment may be required, as the half-life of this drug is about 1 week. There is no antidote to an overdose with semaglutide.

来源:DrugBank

毒理性

• 蛋白质结合

Semaglutide与血浆白蛋白具有高亲和力，促进药物稳定性的高水平。它有超过99%与白蛋白结合。

Semaglutide binds with high affinity to plasma albumin, promoting high levels of drug stability. It is more than 99% bound to albumin.

来源:DrugBank

吸收、分配和排泄

• 吸收

在一项临床试验中，司美格鲁肽的Cmax为10.9 nmol/L，AUC为3123.4 nmol·h/L，Tmax为56小时，在1-3天内达到。该药物的绝对生物利用度为89%。口服片的稳态浓度在4-5周内达到。在0.5mg至1mg剂量范围内，司美格鲁肽的平均稳态浓度从16 nmol/L到30 nmol/L不等。

The Cmax of semaglutide was 10.9 nmol/L, with AUC of 3123.4 nmol h/L and a Tmax of 56 h in one clinical trial, achieved within 1-3 days. The absolute bioavailability is 89%. Steady-state concentration of the oral tablet is achieved in 4-5 weeks. Average steady state concentrations of semaglutide are the mean steady state concentrations after dosing at 0.5mg to 1mg range from 16 nmol/L to 30 nmol/L.

来源:DrugBank

吸收、分配和排泄

• 消除途径

这种药物主要由肾脏清除，在尿液和粪便中均可发现其排出。主要的消除途径是通过尿液，约占摄入放射性剂量的53%，粪便中占18.6%。还有一小部分，约占3.2%，通过呼吸排出。肝功能损害似乎不影响这种药物的清除，因此在肝功能减退的患者中不需要调整剂量。

This drug is mainly cleared by the kidneys, and is found excreted in both the urine and feces. The main elimination route is the urine by corresponding to 53% of an ingested radiolabeled dose, with 18.6% found in the feces. A smaller amount of 3.2% was found to be exhaled. Hepatic impairment does not appear to affect the clearance of this drug and dose adjustments are not required in patients with decreased liver function.

来源:DrugBank

吸收、分配和排泄

• 分布容积

司美格鲁肽的分布容积为8L至9.4L。在大鼠中，它能够通过胎盘。

The volume of distribution of semaglutide is 8L to 9.4L. It crosses the placenta in rats.

来源:DrugBank

吸收、分配和排泄

• 清除

根据一项临床研究，司美格鲁肽的清除率为0.039升/小时。在美国食品药品监督管理局（FDA）的标签上，司美格鲁肽在2型糖尿病患者中的清除率报告为大约0.05升/小时。

The clearance rate of semaglutide is 0.039 L/h according to one clinical study. On the FDA label, semaglutide clearance is reported to be about 0.05 L/h in patients with type 2 diabetes mellitus.

来源:DrugBank