H-D-Arg-Pro-D-Asp-Phe-D-Cys(1)-D-Leu-Glu-D-Pro-Pro-D-Tyr-D-Thr-Gly-Pro-D-Cys(2)-Lys-D-Ala-Arg-Ile-D-Ile-D-Arg-D-Tyr-Phe-D-Tyr-Asn-D-Ala-Lys-D-Ala-Gly-D-Leu-D-Cys(3)-Gln-Thr-Phe-D-Val-Tyr-Gly-Gly-D-Cys(2)-Arg-D-Ala-Lys-Arg-D-Asn-Asn-D-Phe-Lys-D-Ser-Ala-D-Glu-Asp-D-Cys(3)-Met-D-Arg-Thr-Cys(1)-Gly-Gly-D-Ala-OH | 9087-70-1

• 物质功能分类: 生物化工 - 酶及辅酶类
• 分子结构分类: 有机化合物 - 有机聚合物 - 多肽
• 英文名称: H-D-Arg-Pro-D-Asp-Phe-D-Cys(1)-D-Leu-Glu-D-Pro-Pro-D-Tyr-D-Thr-Gly-Pro-D-Cys(2)-Lys-D-Ala-Arg-Ile-D-Ile-D-Arg-D-Tyr-Phe-D-Tyr-Asn-D-Ala-Lys-D-Ala-Gly-D-Leu-D-Cys(3)-Gln-Thr-Phe-D-Val-Tyr-Gly-Gly-D-Cys(2)-Arg-D-Ala-Lys-Arg-D-Asn-Asn-D-Phe-Lys-D-Ser-Ala-D-Glu-Asp-D-Cys(3)-Met-D-Arg-Thr-Cys(1)-Gly-Gly-D-Ala-OH
• 英文别名: (3R)-4-[[(2S)-1-[[(1S,2aS,4S,5aR,8aS,11aS,13R,14aS,16R,17aS,19S,20aR,25R,26aR,29aS,31S,32aR,34R,35aS,37S,38aR,41aS,42R,44aR,45S,47aR,48R,50aR,51S,53aS,54S,56aS,57S,59aR,60R,62aS,63S,66R,69S,72R,75S,78R,81S,84S,87R,90S,93S)-29a,62a,69,84-tetrakis(4-aminobutyl)-35a,75,78-tris(2-amino-2-oxoethyl)-14a-(3-amino-3-oxopropyl)-8a,41a,72-tribenzyl-50a-[(2R)-butan-2-yl]-53a-[(2S)-butan-2-yl]-47a,48,56a,81,90-pentakis(3-carbamimidamidopropyl)-31,60-bis(2-carboxyethyl)-42-[[2-[[2-[[(1R)-1-carboxyethyl]amino]-2-oxoethyl]amino]-2-oxoethyl]carbamoyl]-57-(carboxymethyl)-11a,45-bis[(1R)-1-hydroxyethyl]-13-[(1S)-1-hydroxyethyl]-66-(hydroxymethyl)-2a,16,38a,44a-tetrakis[(4-hydroxyphenyl)methyl]-26a,32a,59a,63,87-pentamethyl-20a,34-bis(2-methylpropyl)-51-(2-methylsulfanylethyl)-1a,3,4a,7a,9,10a,12,13a,15,16a,18,19a,22a,24,25a,28a,30,31a,33,34a,36,37a,40a,43a,44,46a,47,49a,50,52a,53,55a,56,58a,59,61a,62,64a,65,68,71,74,77,80,83,86,89,92,95,98-pentacontaoxo-5a-propan-2-yl-39,40,66a,67a,70a,71a-hexathia-a,2,3a,6a,8,9a,11,12a,14,15a,17,18a,21a,23,24a,27a,29,30a,32,33a,35,36a,39a,42a,43,45a,46,48a,49,51a,52,54a,55,57a,58,60a,61,63a,64,67,70,73,76,79,82,85,88,91,94,97-pentacontazahexacyclo[91.71.4.454,117.04,8.019,23.025,29]doheptacontahectan-37-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]-4-oxobutanoic acid
• CAS: 9087-70-1
• 化学式: C₂₈₄H₄₃₂N₈₄O₇₉S₇
• 分子量: 6511.0
• InChiKey: ZPNFWUPYTFPOJU-YSFZTAPISA-N

物化性质

• 熔点：
  >234oC (dec.)
• 溶解度：
  甘油：可溶性3mg/mL，澄清，无色（含5%甘油的平衡缓冲液）
• 颜色/状态：
  Clear, colorless
• 稳定性/保质期：
  有可透析性，等电点的pH值为10～10.5。该物质对高温、酸和碱都很稳定，在稀酸中加热至100℃、pH=12.6时室温放置24小时仍很稳定；但在pH=12.8时活力会下降。在60～80℃时，它能被嗜热蛋白酶消化，但对其他酶较为稳定。本身不是酶，而是一种广谱抑制剂。

计算性质

• 辛醇/水分配系数(LogP)：
  -25.4
• 重原子数：
  454
• 可旋转键数：
  111
• 环数：
  15.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  2820
• 氢给体数：
  93
• 氢受体数：
  97

ADMET

代谢

抑肽酶会缓慢被溶酶体酶降解。抑肽酶的生理肾脏处理方式与其他小蛋白类似，例如胰岛素。

Aprotinin is slowly degraded by lysosomal enzymes. The physiological renal handling of aprotinin is similar to that of other small proteins, e.g., insulin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在研究中，对九名未经治疗的高血压患者静脉注射剂量为200万KIU的抑肽酶，持续两小时，阻断了100毫克卡托普利引起的急性降压效果。

In study of nine patients with untreated hypertension, /aprotinin/ infused intravenously in a dose of 2 million KIU over two hours blocked the acute hypotensive effect of 100mg of captopril.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

抗纤维蛋白溶解剂和血栓溶解剂的作用是相互拮抗的；尽管在心脏手术前接受过血栓溶解剂的患者中，抑肽酶可能有效预防严重出血...

The actions of antifibrinolytic agents and of thrombolytic agents are mutually antagonistic; although aprotinin may be effective in preventing severe hemorrhage in patients who have received a thrombolytic agent prior to cardiac surgery...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

氨基糖苷类抗生素或改变肾功能药物的并用增加了肾功能障碍和肾衰竭的风险。

Concomitant use of aminoglycoside antibiotics or drugs that alter renal function increased risk of renal dysfunction and renal failure.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

阿普特林干扰了肝素与血小板的结合，并减少了心肺旁路（CPB）期间的血液丢失。肝素在CPB期间消除了血小板的力量，而血小板力量在鱼精蛋白给药后的恢复程度似乎与血液丢失有关。本研究评估了阿普特林对肝素抑制血小板力量的影响。使用Hemodyne止血分析仪测量血小板力量。通过向富血小板血浆（PRP）中添加batroxobin和10 mM CaCl(2)形成血栓。凝血条件包括pH 7.4，离子强度0.15 M，纤维蛋白原水平1 mg/ml和75,000血小板/微升。在凝血1200秒后，力量从7110+/-1190降至450+/-450 dyn，由0.2 U/mL肝素引起。含有阿普特林[20微g/mL（140 KIU/mL）]的PRP中的血小板力量没有被肝素添加所抑制（7480+/-2410 dyn）。将阿普特林[40微g/mL（280 KIU/mL）]添加到先前肝素化的血浆中，抵消了肝素力量的抑制。在没有肝素的情况下，阿普特林（40微g/mL）增加了血小板力量，从5630增加到11,138+/-562。阿普特林不影响凝血酶活性、纤维蛋白结构、血小板聚集或分泌。阿普特林抵消了肝素对血小板力量的抑制，并在没有肝素的情况下增强了血小板力量。阿普特林-肝素-血小板相互作用可能有助于解释阿普特林在CPB期间减少血液丢失的能力。

Aprotinin interferes with heparin binding to platelets and decreases blood loss during cardiopulmonary bypass (CPB). Heparin abolishes platelet force during CPB, and the extent of platelet force recovery after protamine administration appears to correlate with blood loss. This study assessed the effect of aprotinin on heparin suppression of platelet force. Platelet force was measured using the Hemodyne Hemostasis Analyzer. Clots were formed from platelet-rich plasma (PRP) by the addition of batroxobin and 10 mM CaCl(2). Clotting conditions included pH 7.4, ionic strength 0.15 M, fibrinogen level 1 mg/ml and 75,000 platelets/microl. After 1200 s of clotting, force was reduced from 7110+/-1190 to 450+/-450 dyn by 0.2 U/mL of heparin. Platelet force in aprotinin [20 microg/mL (140 KIU/mL)] containing PRP was not suppressed by heparin addition (7480+/-2410 dyn). Aprotinin [40 microg/mL (280 KIU/mL)] addition to previously heparinized plasma counteracted heparin force suppression. Aprotinin (40 microg/mL) increased platelet force from 5630 to 11,138+/-562 in PRP devoid of heparin. Aprotinin did not affect thrombin activity, fibrin structure, platelet aggregation or secretion. Aprotinin counteracts heparin suppression of platelet force and enhances platelet force in the absence of heparin. Aprotinin-heparin-platelet interactions may help explain aprotinin's ability to reduce blood loss during CPB.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

过敏性休克或其他严重过敏反应需要立即进行紧急治疗，包括以下措施：注射肾上腺素；吸氧；注射抗组胺药；静脉注射皮质类固醇；气道管理（包括插管）。

Anaphylaxis or other severe allergic reactions require immediate emergency treatment, which consists of the following : Parenteral epinephrine; Oxygen; Parenteral antihistamines; Intravenous corticosteroids; Airway management (including intubation).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

经静脉（iv）注射后，抗纤溶酶迅速分布到整个细胞外空间，导致血浆中抗纤溶酶浓度迅速初始下降。

After intravenous (iv) injection, rapid distribution of aprotinin occurs into the total extracellular space, leading to a rapid initial decrease in plasma aprotinin concentration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在给予单次静脉注射放射性示踪的抑肽酶后，大约25-40%的放射性物质在48小时内通过尿液排出。在30分钟内输注100万KIU后，大约2%以未改变药物的形态排出。在更大剂量的200万KIU于30分钟内输注后，尿液中未改变的抑肽酶的排出量大约占剂量的9%。

Following a single iv dose of radiolabelled aprotinin, approximately 25-40% of the radioactivity is excreted in the urine over 48 hours. After a 30 minute infusion of 1 million KIU, about 2% is excreted as unchanged drug. After a larger dose of 2 million KIU infused over 30 minutes, urinary excretion of unchanged aprotinin accounts for approximately 9% of the dose.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

动物研究表明，抑肽酶主要在肾脏中积累。抑肽酶在被肾小球过滤后，被近端小管积极重吸收，并储存在吞噬体中。

Animal studies have shown that aprotinin is accumulated primarily in the kidney. Aprotinin, after being filtered by the glomeruli, is actively reabsorbed by the proximal tubules in which it is stored in phagolysosomes.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

目前没有关于抑肽酶分布到母乳中的研究。

There are no available studies on the distribution of aprotinin into breast milk.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn,Xi
• 安全说明：
  S22,S26,S36,S36/37,S45
• 危险类别码：
  R42/43,R36/37/38,R20/21/22
• WGK Germany：
  1
• 海关编码：
  35040000

制备方法与用途

生物活性 Aprotinin是一种丝氨酸蛋白酶的抑制剂（对bovine β-trypsin的Kd值为0.06 pM），用于降低围手术期的失血和输血。

靶点

Target	Value
Thrombin (Cell-free assay)
Trypsin (Cell-free assay)	0.06 pM(Kd)
kallikrein (Cell-free assay)	0.8 nM(Kd)
chymotrypsin (Cell-free assay)	9.5 nM(Kd)
trypsinogen (Cell-free assay)	2 μM(Kd)

体外研究

Aprotinin是一种抗纤维蛋白溶解的小分子，抑制胰蛋白酶和相关的蛋白水解酶。在细胞生物学中，aprotinin被用作蛋白酶抑制剂，在裂解、均化组织和细胞时，防止蛋白降解。Aprotinin以剂量依赖型的方式抑制纤维蛋白溶解活性，同时凝结时间延长。在体外，Aprotinin是一种有效地內源凝血途径抑制剂。

体内研究

Aprotinin在体外抑制血块溶解，在体外延长大鼠剪尾出血时间，在人血浆中延长凝结时间。在大鼠动静脉短路模型中，aprotinin可减少血栓重量。

化学性质

白色或米黄色干燥粉末。易溶于水、生理盐水，不溶于乙醇、丙酮、乙醚。

参考质量标准

• 外观：白色粉末
• 纯度(HPLC) ≥98.0%
• 醋酸根含量≤12.0%
• 水分含量≤8.0%
• 肽含量≥80.0%
• 内毒素≤50EU/mg
• 氨基酸组成分析≤±10%

用途

重组抑肽酶可用作肽酶抑制药，能抑制胰蛋白酶、糜蛋白酶及纤维蛋白溶解酶。用于纤维蛋白溶解现象、急性胰腺炎及胰腺坏死。

生产方法

将新鲜或冰冻的牛肺绞碎，用水提取，加硫酸铵盐析。盐析物用三氯乙酸去杂蛋白，再经透析、脱盐、沉淀等多步操作得到抑肽酶。总收率约23%。