普卡那肽 | 467426-54-6

• 物质功能分类: 原料药 - 消化系统用药 - 胃肠动力药
• 分子结构分类: 有机化合物 - 有机聚合物 - 多肽
• 中文名称: 普卡那肽
• 中文别名: 普来納肽
• 英文名称: Plecanatide
• 英文别名: (2S)-2-[[(1R,4S,7S,10S,13S,16R,19S,22S,25R,32S,38R)-10-(2-amino-2-oxoethyl)-25-[[(2S)-4-carboxy-2-[[(2S)-3-carboxy-2-[[(2S)-2,4-diamino-4-oxobutanoyl]amino]propanoyl]amino]butanoyl]amino]-22-(2-carboxyethyl)-32-[(1R)-1-hydroxyethyl]-4-methyl-19-(2-methylpropyl)-3,6,9,12,15,18,21,24,30,33,36-undecaoxo-7,13-di(propan-2-yl)-27,28,40,41-tetrathia-2,5,8,11,14,17,20,23,31,34,37-undecazabicyclo[14.13.13]dotetracontane-38-carbonyl]amino]-4-methylpentanoic acid
• CAS: 467426-54-6
• 化学式: C₆₅H₁₀₄N₁₈O₂₆S₄
• 分子量: 1681.9
• InChiKey: NSPHQWLKCGGCQR-DLJDZFDSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -8.2
• 重原子数：
  113
• 可旋转键数：
  28
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  819
• 氢给体数：
  23
• 氢受体数：
  31

ADMET

代谢

Plecanatide 在胃肠道中被代谢成一个活性代谢物，通过失去末端的亮氨酸部分。Plecanatide 和其代谢物都在肠腔内被蛋白水解降解成更小的肽和自然存在的氨基酸。

Plecanatide is metabolized in the GI tract to an active metabolite by loss of the terminal leucine moiety. Both plecanatide and the metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids.

来源:DrugBank

代谢

Plecanatide在胃肠道中被代谢成一个活性代谢物，通过失去末端的亮氨酸部分。Plecanatide和这个代谢物都在肠腔内被蛋白水解降解成更小的肽和自然存在的氨基酸。

Plecanatide was metabolized in the GI tract to an active metabolite by loss of the terminal leucine moiety. Both plecanatide and the metabolite were proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

单次口服剂量为0.5 mg/kg和10 mg/kg的plecanatide分别在出生后第7天和第14天的幼年小鼠中引起死亡（相当于人类年龄大约1个月到小于2年）。

Single oral doses of plecanatide at 0.5 mg/kg and 10 mg/kg caused mortality in young juvenile mice on postnatal days 7 and 14, respectively (human age equivalent of approximately 1 month to less than 2 years).

来源:DrugBank

毒理性

• 毒性总结

识别和使用：Plecanatide 是一种白色至灰白色的粉末。它用于治疗：慢性特发性便秘，以及伴有便秘的肠易激综合症。人体研究：Plecanatide 在6岁以下患者中禁忌使用，应避免在18岁以下患者中使用。动物研究：在幼年小鼠中，单次口服给予Plecanatide会导致脱水死亡。Plecanatide的致癌潜力在小鼠和大鼠的两年致癌性研究中进行了评估。在小鼠中，口服剂量高达90 mg/kg/天或在大鼠中口服剂量高达100 mg/kg/天，Plecanatide并未产生肿瘤。在器官形成期给予怀孕小鼠和兔子的Plecanatide，小鼠口服剂量高达800 mg/kg/天，兔子口服剂量高达250 mg/kg/天，未发现对胚胎-胎儿发育有害的证据。在小鼠器官形成期至哺乳期口服给予高达600 mg/kg/天的Plecanatide，未在后代成熟过程中产生发育异常或对生长、学习、记忆或生育的影响。Plecanatide 在小鼠口服剂量高达600 mg/kg/天时，对雄性或雌性小鼠的生育或生殖功能没有影响。Plecanatide 在体外细菌反向突变（Ames）试验、体外小鼠淋巴瘤突变试验或体内小鼠骨髓微核试验中均未表现出基因毒性。

IDENTIFICATION AND USE: Plecanatide is white to off-white powder. It is used for the treatment of: chronic idiopathic constipation, and irritable bowel syndrome with constipation. HUMAN STUDIES: Plecanatide is contraindicated in patients less than 6 years of age, and should be avoided in patients less than 18 years of age. ANIMAL STUDIES: In young juvenile mice, administration of a single oral dose of plecanatide caused deaths due to dehydration. The carcinogenic potential of plecanatide was assessed in 2-year carcinogenicity studies in mice and rats. Plecanatide was not tumorigenic in mice at oral doses up to 90 mg/kg/day or in rats at oral doses up to 100 mg/kg/day. Pregnant mice and rabbits were administered plecanatide during the period of organogenesis. There was no evidence of harm to embryo-fetal development at oral doses up to 800 mg/kg/day in mice and 250 mg/kg/day in rabbits. Oral administration of up to 600 mg/kg/day in mice during organogenesis through lactation produced no developmental abnormalities or effects on growth, learning and memory, or fertility in the offspring through maturation. Plecanatide had no effect on fertility or reproductive function in male or female mice at oral doses of up to 600 mg/kg/day. Plecanatide was not genotoxic in the in vitro bacterial reverse mutation (Ames) assay, in vitro mouse lymphoma mutation assay, or the in vivo mouse bone marrow micronucleus assay.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在上市前的临床试验中，plecanatide治疗期间与血清酶水平升高的情况关联性较低，在接受治疗的受试者中，有1%到2%的人出现了不同程度的血清ALT或AST升高。数值超过正常上限5倍的情况仅有0.2%。在这些研究中，没有出现可以与plecanatide治疗相关联的临床明显的肝损伤并伴有黄疸的病例。自从其获得批准和市场推广以来，没有公开发表的报告指出血清转氨酶升高或临床明显的肝损伤可归因于plecanatide。因此，如果plecanatide导致肝损伤的话，这种情况也一定是罕见的。

In prelicensure clinical trials, plecanatide was associated with low rates of serum enzyme elevations during treatment with some degree of elevation in serum ALT or AST in 1% to 2% of treated subjects. Values rose above 5 times the upper limit of normal in only 0.2%. In these studies, there were no episodes of clinically apparent liver injury with jaundice that could be linked to plecanatide therapy. Since its approval and marketing, there have been no published reports of serum aminotransferase elevations or clinically apparent liver injury attributable to plecanatide. Thus, liver injury from plecanatide must be rare if it occurs at all.

来源:LiverTox

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中和。如果患者停止呼吸，请开始人工呼吸，最好使用需求阀复苏器、球囊阀面罩设备或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果患者呕吐，让患者身体前倾或将其置于左侧（如果可能，头部向下）以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗救助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，辅助通气。通过非重复呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……。监测休克，如有必要，进行治疗……。预防癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的呕吐反射且不流口水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

Plecanatide口服给药后吸收极小，系统利用度几乎可以忽略不计。服用3毫克Plecanatide后，血浆中Plecanatide及其活性代谢物的浓度低于定量限。因此，无法计算诸如药时曲线下面积（AUC）、最大浓度（Cmax）和半衰期（t½）等标准药代动力学参数。

Plecanatide is minimally absorbed with negligible systemic availability following oral administration. Concentrations of plecanatide and its active metabolite in plasma are below the limit of quantitation after an oral dose of 3 mg. Therefore, standard pharmacokinetic parameters such as AUC, maximum concentration (Cmax), and half-life (t½) cannot be calculated.

来源:DrugBank

吸收、分配和排泄

• 消除途径

没有在人体中进行排泄研究。在推荐的临床剂量给药后，Plecanatide及其活性代谢物在血浆中无法测量。

No excretion studies have been conducted in humans. Plecanatide and its active metabolite are not measurable in plasma following administration of the recommended clinical doses.

来源:DrugBank

吸收、分配和排泄

• 分布容积

口服3毫克剂量后，血浆中plecanatide及其活性代谢物的浓度低于定量限，因此无法计算分布体积。

Concentrations of plecanatide and its active metabolite in plasma are below the limit of quantitation after an oral dose of 3 mg. Therefore, the volume of distribution can not be calculated.

来源:DrugBank

吸收、分配和排泄

• 清除

没有在人类中进行过排泄研究。

No excretion studies have been conducted in humans.

来源:DrugBank

吸收、分配和排泄

鉴于在服用临床相关口服剂量后无法测量到plecanatide的浓度，预计plecanatide在组织中的分布将最小化。口服plecanatide定位于胃肠道，在那里它作为鸟苷酸环化酶-C (GC-C)激动剂发挥其作用，系统暴露可忽略不计。Plecanatide表现出与人类血清白蛋白或人类α-1-酸性糖蛋白几乎没有结合。

Given that plecanatide concentrations following clinically relevant oral doses were not measurable, plecanatide is expected to be minimally distributed in tissues. Oral plecanatide was localized to the GI tract where it exerted its effects as a guanylate cyclase-C (GC-C) agonist with negligible systemic exposure. Plecanatide exhibited little to no binding to human serum albumin or human a-1-acid glycoprotein.

来源:Hazardous Substances Data Bank (HSDB)