H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-D-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 | 141758-74-9

• 物质功能分类: 生物化工 - 多肽
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-D-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
• 英文别名: (4S)-5-[[2-[[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-6-amino-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-4-amino-1-[[2-[[2-[(2S)-2-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[(2S)-2-[(2S)-2-[(2S)-2-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]carbamoyl]pyrrolidine-1-carbonyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-2-oxoethyl]amino]-1,4-dioxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-methylsulfanyl-1-oxobutan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-4-[[2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]acetyl]amino]-5-oxopentanoic acid
• CAS: 141758-74-9
• 化学式: C₁₈₄H₂₈₂N₅₀O₆₀S
• 分子量: 4187.0
• InChiKey: HTQBXNHDCUEHJF-JHBIHAKISA-N

物化性质

• 溶解度：
  DMSO 中≥145 mg/mL；不溶于乙醇； ≥52 mg/mL，水溶液，温和加热
• 颜色/状态：
  White to off-white powder
• 稳定性/保质期：

  如果按照规格使用和储存，则不会分解，未有已知危险反应。

计算性质

• 辛醇/水分配系数(LogP)：
  -21
• 重原子数：
  295
• 可旋转键数：
  135
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  1780
• 氢给体数：
  58
• 氢受体数：
  66

ADMET

毒理性

• 毒性总结

识别和使用：艾塞那肽是一种白色至类白色粉末，配制成溶液用于皮下使用。艾塞那肽有两种剂型，一种是每天两次的剂型，另一种是每周一次的缓释剂型。艾塞那肽是一种合成的、长效的人胰高血糖素样肽-1（GLP-1）受体激动剂（肠泌素模拟物）。它作为饮食和运动的辅助手段，用于改善2型糖尿病成年患者的血糖控制。人类暴露和毒性：在一项临床研究中报告了艾塞那肽的过量使用。效果包括严重恶心、严重呕吐和血糖浓度迅速下降。上市后报告还包括急性胰腺炎，包括致命和非致命的出血性或坏死性胰腺炎，需要住院治疗，以及严重的过敏反应（如过敏性休克和血管性水肿）。使用艾塞那肽还报告了肾功能恶化（例如，血清肌酐浓度升高、肾功能不全/不足、慢性肾衰竭、急性肾衰竭有时需要血液透析或肾脏移植）。艾塞那肽缓释剂型在大鼠的临床相关暴露量下也引起了甲状腺C细胞肿瘤。目前尚不清楚该药物是否会在人类中引起甲状腺C细胞肿瘤，包括髓样甲状腺癌（MTC），因为无法通过临床或非临床研究确定对人类的相关性。因此，艾塞那肽缓释剂型禁忌用于有MTC个人或家族史的患者，或患有2型多发性内分泌肿瘤综合征的患者。动物研究：在雄性小鼠中以高达760微克/千克/天的剂量给予艾塞那肽时，对生育能力没有不良影响。然而，艾塞那肽在大鼠、小鼠和家兔中引起了发育毒性。在怀孕大鼠的妊娠第6、9、12和15天皮下给予艾塞那肽缓释剂0.3、1或3毫克/千克时，所有剂量的胎儿生长均减少，并在1和3毫克/千克的剂量下与母体效应（食物摄入量减少和体重增加减少）相关的骨骼钙化不足。在妊娠第6天至第15天（器官发生期）给予6、68、460或760微克/千克/天的皮下剂量的怀孕小鼠中，6微克/千克/天观察到腭裂（有些有孔）和不规则的胎儿肋骨和颅骨骨骼钙化。在妊娠第6天至第18天（器官发生期）给予皮下剂量0.2、2、22、156或260微克/千克/天的怀孕家兔中，2微克/千克/天观察到不规则的胎儿骨骼钙化。还在大鼠中进行了艾塞那肽的致癌性潜力研究。在雌性大鼠中，通过皮下注射18、70或250微克/千克/天的艾塞那肽观察到良性的甲状腺C细胞腺瘤。在另一项艾塞那肽缓释剂的致癌性研究中，每隔一周通过皮下注射0.3、1.0和3.0毫克/千克的剂量的雄性和雌性大鼠。在雌性和雄性中均观察到甲状腺C细胞肿瘤发生率的统计学显著增加。与雄性对照组（13%）和雌性对照组（7%）相比，所有剂量（27%-31%）的雌性和1.0和3.0毫克/千克（分别为46%和47%）的雄性C细胞腺瘤的发生率统计学显著增加。在高剂量组雌性中观察到C细胞癌的发生率统计学显著增加（6%），而在低、中、高剂量组雄性中与对照相比，3%、7%和4%的发生率数值更高（与对照组相比无统计学意义）。在雄性给予3毫克/千克的注射部位皮肤皮下观察到良性纤维瘤的增加。在任何剂量下都没有观察到与治疗相关的注射部位纤维肉瘤。艾塞那肽在Ames细菌突变试验或中国仓鼠卵巢细胞的染色体畸变试验中，无论是否经过代谢激活，均不具有致突变性或断裂性。艾塞那肽在体内小鼠微核试验中呈阴性。

IDENTIFICATION AND USE: Exenatide is a white to off-white powder formulated into solution for subcutaneous use. Exenatide is available in both a twice daily formulation and an extended-release formulation that is administered weekly. Exenatide is a synthetic, long-acting human glucagon-like peptide-1 (GLP-1) receptor agonist (incretin mimetic). It is used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. HUMAN EXPOSURE AND TOXICITY: Overdose of exenatide has been reported in a clinical study. Effects have included severe nausea, severe vomiting, and rapidly declining blood glucose concentrations. Post marketing reports also include acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis requiring hospitalization and serious hypersensitivity reactions (e.g. anaphylaxis and angioedema). Deterioration of renal function (e.g., increased serum creatinine concentrations, renal impairment/insufficiency, and chronic renal failure, acute renal failure sometimes requiring hemodialysis or kidney transplantation) has also been reported with the use of exenatide. Exenatide extended-release also caused thyroid C-cell tumors at clinically relevant exposures in rats. It is unknown whether the drug causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be determined by clinical or nonclinical studies. Therefore, exenatide extended release is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2. ANIMAL STUDIES: Exenatide had no adverse effects on fertility when given to male mice at doses up to 760 ug/kg/day. However, exenatide did cause developmental toxicity in rats, mice and rabbits. Fetuses from pregnant rats given subcutaneous doses of exenatide extended-release at 0.3, 1, or 3 mg/kg on gestation days 6, 9, 12, and 15 demonstrated reduced fetal growth at all doses and produced skeletal ossification deficits at 1 and 3 mg/kg in association with maternal effects (decreased food intake and decreased body weight gain). In pregnant mice given sc doses of 6, 68, 460, or 760 ug/kg/day from gestation day 6 through 15 (organogenesis), cleft palate (some with holes) and irregular fetal skeletal ossification of rib and skull bones were observed at 6 ug/kg/day. In pregnant rabbits given sc doses of 0.2, 2, 22, 156, or 260 ug/kg/day from gestation day 6 through 18 (organogenesis), irregular fetal skeletal ossifications were observed at 2 ug/kg/day. Studies for the carcinogenicity potential of exenatide were also conducted in rats. Benign thyroid C-adenomas were observed in female rats given extenatide by sc injection at doses of 18, 70, or 250 ug/kg/day. In another carcinogenicity study with exenatide extended-release male and female rats were administrated doses of 0.3, 1.0, and 3.0 mg/kg by subcutaneous injection every other week. A statistically significant increase in thyroid C-cell tumor incidence was observed in both males and females. The incidence of C-cell adenomas was statistically significantly increased at all doses (27%-31%) in females and at 1.0 and 3.0 mg/kg (46% and 47%, respectively) in males compared with the control group (13% for males and 7% for females). A statistically significantly higher incidence of C-cell carcinomas occurred in the high-dose group females (6%), while numerically higher incidences of 3%, 7%, and 4% (nonstatistically significant versus controls) were noted in the low-, mid-, and high-dose group males compared with the control group (0% for both males and females). An increase in benign fibromas was seen in the skin subcutis at injection sites of males given 3 mg/kg. No treatment-related injection-site fibrosarcomas were observed at any dose. Exenatide was not mutagenic or clastogenic, with or without metabolic activation, in the Ames bacterial mutagenicity assay or chromosomal aberration assay in Chinese hamster ovary cells. Exenatide was negative in the in vivo mouse micronucleus assay

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

利拉鲁肽引起的肝损伤极为罕见，如果真的发生的话。在大型临床试验中，利拉鲁肽治疗引起的血清酶升高并不比安慰剂或比较剂更常见，而且没有报告出现临床上明显的肝损伤。自从获得许可以来，没有发表过由于利拉鲁肽导致的肝毒性的病例报告，产品标签上也没有列出肝损伤作为不良事件。利拉鲁肽与急性胰腺炎的罕见病例有关联，但即使这种并发症通常也不伴有血清胆红素和转氨酶水平的升高。

Liver injury due to exenatide must be rare, if it occurs at all. In large clinical trials, serum enzyme elevations were no more common with exenatide therapy than with placebo or comparator agents, and no instances of clinically apparent liver injury were reported. Since licensure, there have been no published case reports of hepatotoxicity due to exenatide and the product label does not list liver injury as an adverse event. Exenatide has been linked to rare instances of acute pancreatitis, but even this complication is usually not associated with elevations in serum bilirubin and aminotransferase levels.

来源:LiverTox

毒理性

• 相互作用

在国际标准化比率（INR）增加，有时与出血有关，在exenatide和warfarin联合使用的上市后经验中被报道。在一项药物相互作用研究中，当warfarin钠（单次25毫克剂量）在exenatide（5微克皮下注射，每天两次，持续2天，然后10微克每天两次，持续7天）给药后35分钟给药时，未观察到warfarin（S-或R-对映体）AUC、峰浓度或治疗反应（由INR表示）的临床上重要变化；然而，warfarin浓度峰值时间延迟了大约2小时。在接受warfarin治疗的患者中，在开始或改变exenatide治疗时应更频繁地监测凝血酶原时间；一旦达到稳定的凝血酶原时间，可以在通常推荐接受warfarin治疗的患者的间隔时间内监测凝血酶原时间。

Increases in international normalized ratio (INR), sometimes associated with bleeding, have been reported during postmarketing experience with concomitant use of exenatide and warfarin. In a drug interaction study, no clinically important changes in warfarin (S- or R-enantiomer) AUC, peak plasma concentrations, or therapeutic response (as indicated by INR) were observed when warfarin sodium (single 25-mg dose) was administered 35 minutes after exenatide (5 ug subcutaneously twice daily for 2 days, then 10 ug twice daily for 7 days); however, the time to peak warfarin concentration was delayed by approximately 2 hours. In patients receiving warfarin, prothrombin time should be monitored more frequently after initiating or altering exenatide therapy; once a stable prothrombin time has been achieved, prothrombin times may be monitored at intervals usually recommended for patients receiving warfarin therapy.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在健康女性中，固定组合口服避孕药（30微克炔雌醇和150微克左炔诺孕酮）的重复每日给药，在皮下注射艾塞那肽（每天两次，每次10微克）后30分钟，分别使炔雌醇和左炔诺孕酮的血浆峰浓度降低45%和27%，并且分别延迟炔雌醇和左炔诺孕酮达到血浆峰浓度的时间3小时和3.5小时。在艾塞那肽给药前1小时给予固定组合口服避孕药，使炔雌醇的平均血浆峰浓度降低15%；然而，左炔诺孕酮的平均血浆峰浓度没有显著变化。艾塞那肽在两种方案下重复每日给予固定组合口服避孕药后，没有改变左炔诺孕酮的平均谷浓度；但是，当固定组合口服避孕药在艾塞那肽注射后30分钟给药时，炔雌醇的平均谷浓度增加了20%。在这项研究中，艾塞那肽对口服避孕药药代动力学的影响受到食物可能对口服避孕药影响的混淆。因此，口服避孕药应在艾塞那肽给药前至少1小时给予。

In healthy women, repeated daily administration of a fixed-combination oral contraceptive (30 ug of ethinyl estradiol and 150 ug of levonorgestrel) 30 minutes after subcutaneous injection of exenatide (10 ug twice daily) decreased the peak plasma concentrations of ethinyl estradiol and levonorgestrel by 45 and 27%, respectively, and delayed the time to peak plasma concentrations of ethinyl estradiol and levonorgestrel by 3 and 3.5 hours, respectively. Repeated daily administration of the fixed-combination oral contraceptive 1 hour prior to administration of exenatide decreased the mean peak plasma concentration of ethinyl estradiol by 15%; however, the mean peak plasma concentration of levonorgestrel was not substantially changed. Exenatide did not alter the mean trough concentrations of levonorgestrel following repeated daily administration of the fixed-combination oral contraceptive for both regimens; however, the mean trough concentration of ethinyl estradiol increased by 20% when the fixed-combination oral contraceptive was administered 30 minutes after exenatide injection. In this study, the effect of exenatide on the pharmacokinetics of oral contraceptives was confounded by the possible effect of food on oral contraceptives. Therefore, oral contraceptives should be administered at least 1 hour prior to exenatide administration.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

艾塞那肽（10微克，皮下注射，每日两次）在洛伐他汀（单次口服40毫克剂量）前30分钟给药，使洛伐他汀的AUC（药时曲线下面积）和血浆峰浓度分别降低约40%和28%，并将洛伐他汀达到血浆峰浓度的时间推迟了4小时。在临床试验中，已经接受HMG-CoA还原酶抑制剂（他汀类药物）治疗的患者使用艾塞那肽，与基线相比，并未观察到血脂谱的一致性变化。

Administration of exenatide (10 ug subcutaneously twice daily) 30 minutes before lovastatin (single 40-mg oral dose) decreased the lovastatin AUC and peak plasma concentration by approximately 40 and 28%, respectively, and delayed the time to peak plasma concentration of lovastatin by 4 hours. In clinical trials, the use of exenatide in patients already receiving HMG-CoA reductase inhibitors (statins) was not associated with consistent changes in lipid profiles compared to baseline.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在单次给药Bydureon后，艾塞那肽从微球中大约在10周内释放。首先是表面结合的艾塞那肽释放，随后是微球中艾塞那肽的逐渐释放，这导致在血浆中大约在第2周和第6至7周分别出现两个艾塞那肽的峰值，代表了微球的水化和侵蚀。在开始每周一次（每周）给药2 mg Bydureon后，观察到血浆中艾塞那肽浓度在6到7周内逐渐增加。在6到7周后，平均艾塞那肽浓度在大约300 pg/mL维持，在每个7天（每周）给药间隔内，表明已达到稳态。

Following a single dose of Bydureon, exenatide is released from the microspheres over approximately 10 weeks. There is an initial period of release of surface-bound exenatide followed by a gradual release of exenatide from the microspheres, which results in two subsequent peaks of exenatide in plasma at around week 2 and week 6 to 7, respectively, representing the hydration and erosion of the microspheres. Following initiation of once every 7 days (weekly) administration of 2 mg Bydureon, gradual increase in the plasma exenatide concentration is observed over 6 to 7 weeks. After 6 to 7 weeks, mean exenatide concentrations of approximately 300 pg/mL were maintained over once every 7 days (weekly) dosing intervals indicating that steady state was achieved.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

非临床研究表明，艾塞那肽主要通过肾小球滤过随后发生蛋白水解降解而被消除。艾塞那肽在人中的平均表观清除率为9.1升/小时，平均终末半衰期为2.4小时。艾塞那肽的这些药代动力学特征与剂量无关。在大多数个体中，艾塞那肽浓度在给药后大约10小时内可被测量到。

Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide in humans is 9.1 L/hr and the mean terminal half-life is 2.4 hr. These pharmacokinetic characteristics of exenatide are independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 hr post-dose.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

皮下注射单剂量的Byetta后，艾塞那肽的平均表观分布体积为28.3升。

The mean apparent volume of distribution of exenatide following SC administration of a single dose of Byetta is 28.3 L.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在2型糖尿病患者中，接受艾塞那肽的皮下注射后，艾塞那肽达到中位血浆峰浓度的时间为2.1小时。注射10微克Byetta剂量的艾塞那肽后，平均峰浓度为211皮克/毫升，总体平均药时曲线下面积（AUC0-∞）为1036皮克·小时/毫升。在5微克到10微克的疗效剂量范围内，艾塞那肽的暴露量（AUC）呈比例增加。在同一剂量范围内，Cmax值的增加幅度小于比例增加。在腹部、大腿或上臂进行Byetta的皮下注射，可以相似地达到暴露量。

Following SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 hr. The mean peak exenatide concentration (Cmax) was 211 pg/mL and overall mean area under the time-concentration curve (AUC0-inf) was 1036 pg hr/mL following SC administration of a 10 ug dose of Byetta. Exenatide exposure (AUC) increased proportionally over the therapeutic dose range of 5 ug to 10 ug. The Cmax values increased less than proportionally over the same range. Similar exposure is achieved with SC administration of Byetta in the abdomen, thigh, or upper arm.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• WGK Germany：
  3
• 海关编码：
  2933290000
• 危险品运输编号：
  NONH for all modes of transport

制备方法与用途

新型糖尿病治疗药物

糖尿病是由多种病因引起的以慢性高血糖为特征的代谢紊乱。高血糖主要由胰岛素分泌或作用的缺陷引起，常见类型包括1型糖尿病、2型糖尿病、其他特殊类型糖尿病和妊娠期糖尿病。其中，2型糖尿病患者占绝大多数。

艾塞那肽是一种新型糖尿病治疗药物，由美国礼来公司研发成功，属于肠降血糖素类似物，是肠促胰素类似物家族的第一个成员。它是一种经人工合成的多肽类化合物，可以模拟自然状态下分泌的人胰高血糖素样肽-1 (GLP-1) 在体内的生理行为。艾塞那肽可促进葡萄糖依赖的胰岛素分泌，抑制不适当的葡萄糖依赖性胰高血糖素分泌，并能减慢胃排空、改善外周组织对胰岛素的敏感性，从而有效控制血糖。临床上主要用于治疗二甲双胍、磺酰脲类或二甲双胍和磺酰脲类联合应用不能很好地控制血糖的2型糖尿病患者。

根据美国食品与药品管理局（FDA）不良事件报告系统，在2005年4月28日至2008年10月29日之间，共收到78例有关患者使用艾塞那肽出现肾功能改变的报告。在此期间，美国共开出660多万份艾塞那肽处方。尽管该数据占所有使用药物患者的比例很小，但FDA已完成了对这些病例报告的评估，其中包括62例急性肾功能衰竭病例和16例肾功能不全病例。急性肾功能衰竭或肾功能不全的发生时间范围从用药后三天到两年内，涉及23岁至83岁的患者，平均年龄为60岁。

Exendin-4的作用

Exendin-4能激活GLP-1受体，增加胰腺腺泡细胞内的cAMP水平，但对VIP受体无作用。