(4S)-5-[2-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-6-amino-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-6-amino-1-[(2S)-1-[2-[2-[(2S)-2-[N-[(2S)-1-[(2S)-1-[2-[(2S)-1-[(2S)-2-[(2S)-2-[(2S)-2-[N-[(2S)-1,3-dihydroxy-1-iminopropan-2-yl]-C-hydroxycarbonimidoyl]pyrrolidine-1-carbonyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]imino-2-hydroxyethyl]imino-1,3-dihydroxypropan-2-yl]imino-1,3-dihydroxypropan-2-yl]-C-hydroxycarbonimidoyl]pyrrolidin-1-yl]-2-oxoethyl]imino-2-hydroxyethyl]imino-1,4-dihydroxy-4-iminobutan-2-yl]imino-1-hydroxyhexan-2-yl]imino-1-hydroxy-4-methylpentan-2-yl]imino-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl]imino-4-carboxy-1-hydroxybutan-2-yl]imino-1-hydroxy-3-methylpentan-2-yl]imino-1-hydroxy-3-phenylpropan-2-yl]imino-1-hydroxy-4-methylpentan-2-yl]imino-5-carbamimidamido-1-hydroxypentan-2-yl]imino-1-hydroxy-3-methylbutan-2-yl]imino-1-hydroxypropan-2-yl]imino-4-carboxy-1-hydroxybutan-2-yl]imino-4-carboxy-1-hydroxybutan-2-yl]imino-4-carboxy-1-hydroxybutan-2-yl]imino-1-hydroxy-4-methylsulfanylbutan-2-yl]imino-1,5-dihydroxy-5-iminopentan-2-yl]imino-1-hydroxyhexan-2-yl]imino-1,3-dihydroxypropan-2-yl]imino-1-hydroxy-4-methylpentan-2-yl]imino-3-carboxy-1-hydroxypropan-2-yl]imino-1,3-dihydroxypropan-2-yl]imino-1,3-dihydroxybutan-2-yl]imino-1-hydroxy-3-phenylpropan-2-yl]imino-1,3-dihydroxybutan-2-yl]imino-2-hydroxyethyl]imino-4-[[2-[[(2S)-2-amino-1-hydroxy-3-(1H-imidazol-5-yl)propylidene]amino]-1-hydroxyethylidene]amino]-5-hydroxypentanoic acid

• 分子结构分类: 有机化合物 - 有机聚合物 - 多肽
• 英文名称: (4S)-5-[2-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-6-amino-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-6-amino-1-[(2S)-1-[2-[2-[(2S)-2-[N-[(2S)-1-[(2S)-1-[2-[(2S)-1-[(2S)-2-[(2S)-2-[(2S)-2-[N-[(2S)-1,3-dihydroxy-1-iminopropan-2-yl]-C-hydroxycarbonimidoyl]pyrrolidine-1-carbonyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]imino-2-hydroxyethyl]imino-1,3-dihydroxypropan-2-yl]imino-1,3-dihydroxypropan-2-yl]-C-hydroxycarbonimidoyl]pyrrolidin-1-yl]-2-oxoethyl]imino-2-hydroxyethyl]imino-1,4-dihydroxy-4-iminobutan-2-yl]imino-1-hydroxyhexan-2-yl]imino-1-hydroxy-4-methylpentan-2-yl]imino-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl]imino-4-carboxy-1-hydroxybutan-2-yl]imino-1-hydroxy-3-methylpentan-2-yl]imino-1-hydroxy-3-phenylpropan-2-yl]imino-1-hydroxy-4-methylpentan-2-yl]imino-5-carbamimidamido-1-hydroxypentan-2-yl]imino-1-hydroxy-3-methylbutan-2-yl]imino-1-hydroxypropan-2-yl]imino-4-carboxy-1-hydroxybutan-2-yl]imino-4-carboxy-1-hydroxybutan-2-yl]imino-4-carboxy-1-hydroxybutan-2-yl]imino-1-hydroxy-4-methylsulfanylbutan-2-yl]imino-1,5-dihydroxy-5-iminopentan-2-yl]imino-1-hydroxyhexan-2-yl]imino-1,3-dihydroxypropan-2-yl]imino-1-hydroxy-4-methylpentan-2-yl]imino-3-carboxy-1-hydroxypropan-2-yl]imino-1,3-dihydroxypropan-2-yl]imino-1,3-dihydroxybutan-2-yl]imino-1-hydroxy-3-phenylpropan-2-yl]imino-1,3-dihydroxybutan-2-yl]imino-2-hydroxyethyl]imino-4-[[2-[[(2S)-2-amino-1-hydroxy-3-(1H-imidazol-5-yl)propylidene]amino]-1-hydroxyethylidene]amino]-5-hydroxypentanoic acid
• 化学式: C₁₈₄H₂₈₂N₅₀O₆₀S
• 分子量: 4187.0
• InChiKey: HTQBXNHDCUEHJF-URRANESESA-N

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

• 肝毒性

利拉鲁肽引起的肝脏损伤必须很罕见，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明显的肝脏损伤。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，产品标签也未将肝脏损伤列为不良事件。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，每日两次，持续2天，然后10微克每日两次，持续7天）给药后35分钟给药时，未观察到warfarin（S-或R-对映体）的AUC、峰浓度或治疗反应（由INR表示）的临床上重要变化；然而，warfarin达到峰浓度的时间延迟了大约2小时。在接受warfarin治疗的患者中，在开始或改变exenatide治疗后的前几周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，可以按照通常推荐给接受warfarin治疗的患者的时间间隔进行监测。

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

在健康的女性中，每天重复给予固定组合口服避孕药（30微克炔雌醇和150微克左炔诺孕酮）在皮下注射艾塞那肽（每天两次，每次10微克）后30分钟，炔雌醇和左炔诺孕酮的血浆峰浓度分别降低了45%和27%，并且炔雌醇和左炔诺孕酮达到血浆峰浓度的时间分别延迟了3小时和3.5小时。在给予艾塞那肽前1小时重复给予固定组合口服避孕药，炔雌醇的平均血浆峰浓度降低了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天给予固定组合口服避孕药后，并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分钟给予时，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，每天两次皮下注射）在洛伐他汀（单次口服40毫克剂量）前30分钟给药，大约使洛伐他汀的AUC（药时曲线下面积）和血浆峰值浓度分别降低40%和28%，并将洛伐他汀达到血浆峰值浓度的时间推迟了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)

毒理性

• 相互作用

在接受稳定剂量的赖诺普利（每天5-20毫克）的轻至中度高血压患者中，艾塞那肽（每天两次皮下注射10微克）并未改变赖诺普利的稳态曲线下面积（AUC）或峰浓度，也未改变24小时平均收缩压和舒张压。然而，赖诺普利的稳态达峰时间延迟了2小时。

In patients with mild to moderate hypertension receiving stable dosages of lisinopril (5-20 mg daily), exenatide (10 ug subcutaneously twice daily) did not alter the steady-state AUC or peak plasma concentration of lisinopril or the 24-hour mean systolic and diastolic blood pressure. However, the steady-state time to peak plasma concentration of lisinopril was delayed by 2 hours.

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，在每周一次（每周）给药间隔期内，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蛋白水解降解而消除。艾塞那肽在人体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性与剂量无关。在大多数个体中，艾塞那肽浓度在给药后约10小时可检测到。

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

皮下注射单次剂量的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

在给2型糖尿病患者皮下注射艾塞那肽后，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剂量的平均峰浓度（Cmax）为211皮克/毫升，总的平均药时曲线下面积（AUC0-inf）为1036皮克·小时/毫升。艾塞那肽的暴露量（AUC）在5微克到10微克的治療剂量范围内成比例增加。Cmax值在同一剂量范围内的增加幅度小于成比例。在腹部、大腿或上臂皮下注射Byetta可以达到相似的暴露量。

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)