普拉格雷 | 150322-43-3

• 物质功能分类: 原料药 - 血液系统用药 - 抗凝血药及抗血小板药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩并吡啶类
• 中文名称: 普拉格雷
• 中文别名: 普拉格雷中间体-2；2-[2-(乙酰氧基)-6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基]-1-环丙基-2-(2-氟苯基)乙酮；5-[2-环丙基-1-(2-氟苯基)-2-氧乙基]-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基羧酸酯
• 英文名称: prasugel
• 英文别名: Prasugrel；5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxoethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate；5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate；2-[2-(acetyloxy)-6,7-di-hydrothieno[3,2-c]-pyridin-5(4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl)ethanone；2-acetoxy-5-(2-fluoro-α-cyclopropylcarbonylbenzyl)-4,5,6,7-tetrahydro-4H-thieno[3.2-c]pyridine；2-acetoxy-5-(2-fluoro-α-cyclopropylcarbonylbenzyl)-4,5,6,7-tetrahydro-4H-tieno[3,2-c]pyridine；[5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-6,7-dihydro-4H-thieno[3,2-c]pyridin-2-yl] acetate
• CAS: 150322-43-3
• 化学式: C₂₀H₂₀FNO₃S
• 分子量: 373.448
• InChiKey: DTGLZDAWLRGWQN-UHFFFAOYSA-N

物化性质

• 熔点：
  120.0 to 124.0 °C
• 沸点：
  493.5±45.0 °C(Predicted)
• 密度：
  1.347
• 溶解度：
  DMSO：>5mg/mL（加热至 60 °C）
• 物理描述：
  Solid
• 蒸汽压力：
  7.33X10-9 mm Hg at 25 °C (est)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  74.8
• 氢给体数：
  0
• 氢受体数：
  6

ADMET

代谢

Prasugrel口服给药后未在血浆中检测到。它在肠道中被人类羧酸酯酶2（hCE2）迅速水解为硫内酯。这一中间体随后在肝脏中通过细胞色素P450酶（主要是CYP3A4和CYP2B6，其次是CYP2C9和CYP2C19）一步转化为其活性代谢物R-138727。活性代谢物进一步通过S-甲基化或半胱氨酸结合转化为两种非活性代谢物。与氯吡格雷不同，普拉格雷转化为其活性代谢物似乎不受细胞色素P450多态性的影响。

Prasugrel is not detected in plasma following oral administration. It is rapidly hydrolyzed in the intestine to thiolactone by human carboxylesterase (hCE) 2. This intermediate is further metabolized to its active metabolite, R-138727, in a single step by cytochrome P450 enzymes in the liver (primarily CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19). The active metabolite is further metabolized by S-methylation or cysteine conjugation to two inactive metabolites. Unlike clopidogrel, transformation of prasugrel to its active metabolite does not appear to be affected by cytochrome P450 polymorphisms.

来源:DrugBank

代谢

Prasugrel在所有物种中被广泛代谢。在人类血浆中总共鉴定出十八种代谢物。基于平均放射活性超过10%，可以鉴定出以下主要代谢物：M1、M2（R-95913）和M5（R-106583）的对映异构体。在人类血浆、尿液和粪便中发现的prasugrel的代谢物也在小鼠、大鼠和狗中检测到；唯一的例外是M16，它仅在鼠标中鉴定到。M16是M10与葡萄糖醛酸结合的产物，而M10在所有物种中都有发现。此外，特定代谢物的形成程度在不同物种之间有显著差异。代谢物M1在人类中大量形成，在动物血浆中也有检测到，但由于放射性峰的共洗脱，在动物中没有进行量化。与动物物种相比，代谢物M2、M5、M7和M14在人类中也以较大量形成。

Prasugrel was extensively metabolised in all species. A total of eighteen metabolites were identified in human plasma. Based on a mean radioactivity above 10%, the following major metabolites could be identified: diastereomers of M1, M2 (R-95913) and M5 (R-106583). The metabolites of prasugrel found in human plasma, urine and faeces were also detected in mouse, rat and dog; the only exception being M16, which was only identified in the mouse. M16 is M10 conjugated to glucuronic acid and M10 was found in all species. Furthermore, the extent of formation of a given metabolite varied significantly by species. Metabolite M1 was formed in large amounts in humans and was detected in animal plasma, but quantification was not conducted in animals due to co-eluting of the radioactive peaks. Metabolites M2, M5, M7 and M14 were also formed in larger amounts in humans as compared to the animal species.

来源:Hazardous Substances Data Bank (HSDB)

代谢

Prasugrel口服给药后在血浆中检测不到。它在肠道中迅速水解为硫内酯，然后通过一步转化为活性代谢物，主要由CYP3A4和CYP2B6催化，其次由CYP2C9和CYP2C19催化。prasugrel活性代谢物的表观分布容积估计值为44至68升，表观清除率估计值为112至166升/小时，在健康受试者和稳定动脉粥样硬化患者中。活性代谢物通过S-甲基化或与半胱氨酸结合转化为两种非活性化合物。主要的非活性代谢物高度结合于人血浆蛋白。大约68%的prasugrel剂量以非活性代谢物的形式从尿液中排出，27%从粪便中排出。

Prasugrel is not detected in plasma following oral administration. It is rapidly hydrolyzed in the intestine to a thiolactone, which is then converted to the active metabolite by a single step, primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. The estimates of apparent volume of distribution of prasugrel's active metabolite ranged from 44 to 68 L and the estimates of apparent clearance ranged from 112 to 166 L/hr in healthy subjects and patients with stable atherosclerosis. The active metabolite is metabolized to two inactive compounds by S-methylation or conjugation with cysteine. The major inactive metabolites are highly bound to human plasma proteins. Approximately 68% of the prasugrel dose is excreted in the urine and 27% in the feces as inactive metabolites.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在大鼠中，当给予高剂量（大于或等于100 mg/kg）普拉格雷时，会诱导CYP450酶（CYP2B和CYP3A2）和II相代谢酶UDP-葡萄糖醛酸基转移酶和谷胱甘肽-S-转移酶，然而，基于用人肝细胞进行的体外非临床研究，这种诱导在人类中并未观察到。此外，与小鼠在大于或等于100 mg/kg/天、大鼠在100和300 mg/kg/天、以及狗在20 mg/kg/天（在20周给药及以后）第一次给药后获得的值相比，每个测量到的代谢物的AUC在多次给药后有所下降。然而，在狗中给予普拉格雷20 mg/kg一个月的暴露数据基本上没有变化。在狗的九个月研究中，两种代谢物R-100932和R-106583在20周给药后的AUC数据下降，而另一种代谢物R-95913在给予普拉格雷20 mg/kg的狗中的AUC值更高。因此，数据显示在狗中以20 mg/kg剂量给予普拉格雷时，会有一些自我诱导普拉格雷代谢的现象。

When administered at high doses ( > or = 100 mg/kg) to rats, prasugrel induced CYP450 enzymes (CYP2B and CYP3A2) and phase II metabolizing enzymes UDP-glucuronosyltransferase and glutathione- S-transferase, however, based on the in vitro non clinical study with human hepatocytes, this induction is not observed in humans. Furthermore, the AUC for each measured metabolite decreased after multiple dosing compared with the values obtained after the first dose in mice at > or = 100 mg/kg/day, in rats at 100 and 300 mg/kg/day, and in dogs at 20 mg/kg/day (after 20 weeks of dosing and beyond). However, the exposure data in dogs administered prasugrel at 20 mg/kg for one month were essentially unchanged. In the nine month study with dogs, the AUC data for two of the metabolites R-100932 and R-106583 decreased after 20 weeks of dosing, while the AUC values of the other metabolite, R-95913 were higher in dogs dosed with prasugrel at 20 mg/kg. Thus, the data show some auto-induction of prasugrel's metabolism at the 20-mg/kg dose in dogs.

来源:Hazardous Substances Data Bank (HSDB)

代谢

Prasugrel ... 在体内迅速水解为硫内酯，R-95913，后者通过细胞色素P450（P450）的氧化作用进一步转化为含有巯基的药理活性代谢物，R-138727。我们在含有硫内酯R-95913、表达的CYP3A4和NADPH的孵化混合物中，以2-硝基-5-硫基苯甲酸与亚磺酸代谢物形成混合二硫化物。进一步的实验研究了亚磺酸转化为活性巯基代谢物的一种可能机制。当存在谷胱甘肽时，R-138727与谷胱甘肽形成的混合二硫化物形式可能是R-138727的前体。当向人肝微粒体中添加人肝细胞质时，谷胱甘肽共轭物R-138727还原为R-138727的速率常数增加。因此，R-138727在体外最终形成的可能机制之一是通过P450介导形成亚磺酸，然后可能通过谷胱甘肽共轭形成混合二硫化物，并还原二硫化物为活性代谢物R-138727。

Prasugrel ... undergoes rapid hydrolysis in vivo to a thiolactone, R-95913, which is further converted to its thiol-containing, pharmacologically active metabolite, R-138727, by oxidation via cytochromes P450 (P450). We trapped a sulfenic acid metabolite as a mixed disulfide with 2-nitro-5-thiobenzoic acid in an incubation mixture containing the thiolactone R-95913, expressed CYP3A4, and NADPH. Further experiments investigated one possible mechanism for the conversion of the sulfenic acid to the active thiol metabolite in vitro. A mixed disulfide form of R-138727 with glutathione was found to be a possible precursor of R-138727 in vitro when glutathione was present. The rate constant for the reduction of the glutathione conjugate of R-138727 to R-138727 was increased by addition of human liver cytosol to the human liver microsomes. Thus, one possible mechanism for the ultimate formation of R-138727 in vitro can be through formation of a sulfenic acid mediated by P450s followed possibly by a glutathione conjugation to a mixed disulfide and reduction of the disulfide to the active metabolite R-138727.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

普拉格雷在治疗期间与低血清酶升高率相关，这与氯吡格雷相似。在上市前的研究中，没有报告出现临床上明显的肝损伤。自从上市和发布以来，已经有多起因普拉格雷引起的肝损伤的报告，通常是由于超敏反应的一部分。从氯吡格雷转换为普拉格雷后几周内出现症状，伴随轻至中度ALT和GGT升高，一旦将普拉格雷替换为氯吡格雷，这些症状就会迅速缓解。肝损伤被超敏综合症的特征所掩盖，包括发热、嗜酸性粒细胞增多和腹泻，停止使用普拉格雷后这些症状也会迅速逆转。没有报告出现自身抗体。还有一例报告了肝细胞性黄疸的病例，只有在停止使用普拉格雷后才得以解决。尽管氯吡格雷和替格瑞洛有报告出现慢性损伤或急性肝衰竭的情况，但尚未有普拉格雷相关的报告。

Prasugrel is associated with low rates of serum enzyme elevations during therapy, which are similar to those with clopidogrel. In premarketing studies, no instances of clinically apparent liver injury were reported. Since marketing and release, there has been several reports of liver injury attributed to prasugrel often as a part of a hypersensitivity reaction. The onset was within a few weeks of switching from clopidogrel to prasugrel, and was accompanied by mild-to-moderate ALT and GGT elevations that resolved rapidly once prasugrel was replaced by clopidogrel. The liver injury was overshadowed by features of a hypersensitivity syndrome with fever, eosinophilia and diarrhea, which also reversed rapidly with stopping prasugrel. Autoantibodies were not reported. There has also been one report of a case of hepatocellular jaundice that resolved only after stopping prasugrel. There have been no reports of chronic injury or acute liver failure reported with prasugrel, although such instances have been reported with clopidogrel and ticlopidine.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：目前没有关于在母乳喂养期间使用普拉格雷的信息。在获得更多信息之前，特别是在哺乳新生儿或早产儿时，应谨慎使用普拉格雷。如果哺乳母亲使用，应监测婴儿是否有瘀伤和出血。 ◉ 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:No published information is available on the use of prasugrel during breastfeeding. Until more data become available, prasugrel should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant. If it is used by a nursing mother, monitor the infant for bruising and bleeding. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

接受华法林同时治疗的患者的出血风险增加。同时给予单次15毫克华法林剂量的情况下，出血时间显著延长。

Increased risk of bleeding in patients receiving concomitant therapy with warfarin. Bleeding time substantially prolonged with concomitant administration of a single 15-mg dose of warfarin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

与溶栓剂同时使用时，出血风险增加。

Increased risk of bleeding with concomitant use /of thrombolytic agents/.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

与阿司匹林或其他非甾体抗炎药（NSAIDs）长期联合使用时，出血风险增加。

Increased risk of bleeding with concomitant long-term use of aspirin or other nonsteroidal anti-inflammatory agents (NSAIAs).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

口服给药后，79%或更多的剂量被吸收。吸收和代谢发生迅速，口服给药后大约30分钟达到血浆峰浓度（Cmax）。在高脂肪、高热量餐后给药不影响健康个体中活性代谢物的AUC，但Cmax降低了约49%，Tmax延长至0.5到1.5小时。普拉格雷可以在有或没有食物的情况下给药。

79% or greater of the dose is absorbed after oral administration. Absorption and metabolism occur rapidly and peak plasma concentrations (Cmax) are reached approximately 30 minutes following oral administration. Administration with a high fat, high calorie meal did not affect the AUC of the active metabolite in healthy individuals, but the Cmax was decreased by ~49% and the Tmax was increased to 0.5 to 1.5 hours. Prasugrel may be administered with or without food.

来源:DrugBank

吸收、分配和排泄

• 消除途径

大约68%的口服给药剂量以无活性代谢物的形式通过尿液排出，27%通过粪便排出。活性代谢物预计不会通过透析被清除。

Approximately 68% of the orally administered dose is excreted in urine and 27% in the feces, as inactive metabolites. The active metabolite is not expected to be removed by dialysis.

来源:DrugBank

吸收、分配和排泄

• 分布容积

44-68L

44-68L

来源:DrugBank

吸收、分配和排泄

• 清除

表观清除率 = 112 - 166 升/小时

Apparent clearance = 112 - 166 L/hr

来源:DrugBank

吸收、分配和排泄

在单次和重复口服给予大鼠普拉格雷后，研究了与普拉格雷相关的放射性在组织中的分布。放射性物质在体内广泛且迅速分布。在吸收和消除化合物及其代谢物的大多数组织中，放射性浓度最高，例如胃、肠、肝、肾和膀胱。普拉格雷分布到大鼠的骨髓中，组织与血浆的比值小于0.5。在重复每日给药后，观察到与普拉格雷消除半衰期一致的累积现象，在大多数器官中都有体现。

Tissue distribution of radioactivity related to prasugrel was studied in rats following single and repeated oral administration. Radioactivity was widely and rapidly distributed throughout the body. The radioactivity concentration was highest in most tissues involved in the absorption and elimination of the compound and its metabolites, i.e., stomach, intestines, liver, kidney and urinary bladder. Prasugrel distributed to the bone marrow of rats with a tissue-to-plasma ratio of less than 0.5. Following repeated daily dosing, accumulation consistent with the elimination half-life of prasugrel was observed in most organs.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S24/25
• WGK Germany：
  3
• 海关编码：
  29349990
• 危险品运输编号：
  NONH for all modes of transport
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  2-8°C

SDS

普拉格雷 修改号码：5

---

模块 1. 化学品
产品名称： Prasugrel
修改号码： 5

---

模块 2. 危险性概述
GHS分类
物理性危害 未分类
健康危害 未分类
环境危害 未分类
GHS标签元素
图标或危害标志 无
信号词 无信号词
危险描述 无
防范说明 无

---

模块 3. 成分/组成信息
单一物质/混和物 单一物质
化学名(中文名)： 普拉格雷
百分比： >98.0%(LC)(T)
CAS编码： 150322-43-3
俗名： 5-[2-Cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-
tetrahydrothieno[3,2-c]pyridin-2-yl Acetate
分子式： C20H20FNO3S

---

模块 4. 急救措施
吸入： 将受害者移到新鲜空气处，保持呼吸通畅，休息。若感不适请求医/就诊。
皮肤接触： 立即去除/脱掉所有被污染的衣物。用水清洗皮肤/淋浴。
若皮肤刺激或发生皮疹：求医/就诊。
眼睛接触： 用水小心清洗几分钟。如果方便，易操作，摘除隐形眼镜。继续清洗。
如果眼睛刺激：求医/就诊。
食入： 若感不适，求医/就诊。漱口。
紧急救助者的防护： 救援者需要穿戴个人防护用品，比如橡胶手套和气密性护目镜。

---

模块 5. 消防措施
合适的灭火剂： 干粉，泡沫，雾状水，二氧化碳
普拉格雷 修改号码：5

---

模块 5. 消防措施
特殊危险性： 小心，燃烧或高温下可能分解产生毒烟。
特定方法： 从上风处灭火，根据周围环境选择合适的灭火方法。
非相关人员应该撤离至安全地方。
周围一旦着火：如果安全，移去可移动容器。
消防员的特殊防护用具： 灭火时，一定要穿戴个人防护用品。

---

模块 6. 泄漏应急处理
个人防护措施，防护用具， 使用个人防护用品。远离溢出物/泄露处并处在上风处。
紧急措施： 泄露区应该用安全带等圈起来，控制非相关人员进入。
环保措施： 防止进入下水道。
控制和清洗的方法和材料： 清扫收集粉尘，封入密闭容器。注意切勿分散。附着物或收集物应该立即根据合适的
法律法规处置。

---

模块 7. 操作处置与储存
处理
技术措施： 在通风良好处进行处理。穿戴合适的防护用具。防止粉尘扩散。处理后彻底清洗双手
和脸。
注意事项： 如果粉尘或浮质产生，使用局部排气。
操作处置注意事项： 避免接触皮肤、眼睛和衣物。
贮存
储存条件： 保持容器密闭。冷藏储存。
远离不相容的材料比如氧化剂存放。
热敏
包装材料： 依据法律。

---

模块 8. 接触控制和个体防护
工程控制： 尽可能安装封闭体系或局部排风系统，操作人员切勿直接接触。同时安装淋浴器和洗
眼器。
个人防护用品
呼吸系统防护： 防尘面具。依据当地和政府法规。
手部防护： 防护手套。
眼睛防护： 安全防护镜。如果情况需要，佩戴面具。
皮肤和身体防护： 防护服。如果情况需要，穿戴防护靴。

---

模块 9. 理化特性
固体
外形（20°C）：
外观： 晶体-粉末
颜色： 微浅黄色-红黄色
气味： 无资料
pH: 无数据资料
熔点：
122°C
沸点/沸程 无资料
闪点： 无资料
爆炸特性
爆炸下限： 无资料
爆炸上限： 无资料
密度： 无资料
溶解度：
[水] 无资料
普拉格雷 修改号码：5

---

模块 9. 理化特性
[其他溶剂] 无资料
log水分配系数 = 3.92

---

模块 10. 稳定性和反应性
化学稳定性： 一般情况下稳定。
危险反应的可能性： 未报道特殊反应性。
须避免接触的物质 氧化剂
危险的分解产物: 一氧化碳, 二氧化碳, 氮氧化物 (NOx), 氟化氢, 硫氧化物

---

模块 11. 毒理学信息
急性毒性： 无资料
对皮肤