[(1S,4R)-4-[2-amino-6-(cyclopropylamino)-7H-purin-9-ium-9-yl]cyclopent-2-en-1-yl]methanol;sulfate | 188062-50-2

• 物质功能分类: 原料药 - 人工合成抗感染类药 - 抗病毒类药
• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 核苷和核苷酸类似物
• 英文名称: [(1S,4R)-4-[2-amino-6-(cyclopropylamino)-7H-purin-9-ium-9-yl]cyclopent-2-en-1-yl]methanol;sulfate
• CAS: 188062-50-2
• 化学式: C28H38N12O6S
• 分子量: 670.7
• InChiKey: WMHSRBZIJNQHKT-FFKFEZPRSA-N

物化性质

• 熔点：
  222-225°C
• 溶解度：
  H2O：≥17mg/mL
• 颜色/状态：
  White to off-white solid

计算性质

• 辛醇/水分配系数(LogP)：
  1.53
• 重原子数：
  47
• 可旋转键数：
  8
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  287
• 氢给体数：
  8
• 氢受体数：
  16

ADMET

代谢

阿巴卡韦部分通过醇脱氢酶（形成5'-羧酸）和葡萄糖醛酸化（形成5'-葡萄糖醛酸苷）进行代谢。

Abacavir is partially metabolized by alcohol dehydrogenase (to form the 5'-carboxylic acid) and glucuronidation (to form the 5'-glucuronide).

来源:Hazardous Substances Data Bank (HSDB)

代谢

阿巴卡韦的代谢命运尚未完全确定，但该药物在肝脏中代谢。阿巴卡韦通过醇脱氢酶代谢形成5-羧酸，通过葡萄糖醛酸转移酶代谢形成5-葡萄糖苷酸；这些代谢物似乎没有抗病毒活性。细胞色素P450同工酶在阿巴卡韦代谢中的参与是有限的。

The metabolic fate of abacavir has not been fully determined, but the drug is metabolized in the liver. Abacavir is metabolized by alcohol dehydrogenase to form the 5-carboxylic acid and by glucuronyltransferase to form the 5-glucuronide; these metabolites do not appear to have any antiviral activity. Any involvement of cytochrome p450 isoenzymes in the metabolism of abacavir is limited.

来源:Hazardous Substances Data Bank (HSDB)

代谢

细胞内，阿巴卡韦通过腺苷酸转移酶磷酸化生成阿巴卡韦单磷酸盐；然后阿巴卡韦单磷酸盐在细胞质酶催化的反应中转化为卡波维单磷酸盐，接着通过细胞激酶转化为卡波维三磷酸盐。阿巴卡韦到卡波维三磷酸盐的细胞内（宿主细胞）转化是药物发挥抗病毒活性的必要条件。在CD4+ CEM细胞中，卡波维三磷酸盐的体外半衰期为3.3小时。

Intracellularly, abacavir is phosphorylated to abacavir monophosphate by adenosine phosphotransferase; abacavir monophosphate is then converted to carbovir monophosphate in a reaction catalyzed by cytosolic enzymes and then to carbovir triphosphate by cellular kinases. Intracellular (host cell) conversion of abacavir to carbovir triphosphate is necessary for the antiviral activity of the drug. The in vitro intracellular half-life of carbovir triphosphate in CD4+ CEM cells is 3.3 hours.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：阿巴卡韦在母乳中以小量出现。关于其在哺乳期使用的安全性信息非常有限。在美国和其他可以获取清洁水源和负担得起的替代喂养的国家，建议感染HIV的母亲不要母乳喂养婴儿，以避免HIV-1感染的后天传播。通过抗逆转录病毒治疗实现并维持病毒载量抑制，可以将母乳喂养传播风险降低到小于1%，但并非零。在抗逆转录病毒治疗下，病毒载量持续不可检测的HIV感染者如果选择母乳喂养，应支持这一决定。 ◉ 对母乳喂养婴儿的影响：一名HIV阳性母亲每天服用一次含有多替拉韦50mg、硫酸阿巴卡韦600mg和拉米夫定300mg（特鲁迈克）的复合片剂。她的婴儿大约纯母乳喂养了30周，然后又部分母乳喂养了大约20周。未观察到明显的副作用。 ◉ 对泌乳和母乳的影响：在接受高效抗逆转录病毒治疗的男性中报告了男性乳房发育。男性乳房发育最初是单侧的，但在大约一半的病例中进展为双侧。未观察到血清催乳素的变化，即使继续用药，通常也会在一年内自发解决。一些病例报告和体外研究建议蛋白酶抑制剂可能会在某些男性患者中引起高催乳素血症和乳汁分泌过多，尽管这一点存在争议。这些发现与哺乳母亲的相关性尚不清楚。已建立泌乳的母亲催乳素水平可能不会影响她的哺乳能力。

◉ Summary of Use during Lactation:Abacavir appears in breastmilk in small quantities. Very little information is available on the safety of its use during breastfeeding. In the US and other countries where access to clean water and affordable replacement feeding are available, it is recommended that mothers living with HIV not breastfeed their infants to avoid postnatal transmission of HIV-1 infection. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. ◉ Effects in Breastfed Infants:An HIV-positive mother took a combination tablet containing dolutegravir 50 mg, abacavir sulfate 600 mg and lamivudine 300 mg (Triumeq) once daily. Her infant was exclusively breastfed for about 30 weeks and partially breastfed for about 20 weeks more. No obvious side effects were noted. ◉ Effects on Lactation and Breastmilk:Gynecomastia has been reported among men receiving highly active antiretroviral therapy. Gynecomastia is unilateral initially, but progresses to bilateral in about half of cases. No alterations in serum prolactin were noted and spontaneous resolution usually occurred within one year, even with continuation of the regimen. Some case reports and in vitro studies have suggested that protease inhibitors might cause hyperprolactinemia and galactorrhea in some male patients, although this has been disputed. The relevance of these findings to nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

同时使用乙醇与阿巴卡韦可能会导致阿巴卡韦的浓度和半衰期增加，这是由于酒精脱氢酶通过共同代谢途径竞争所致。

Concurrent use /of ethanol/ with abacavir may result in increased concentrations and half-life of abacavir as a result of competition for common metabolic pathways via alcohol dehydrogenase.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在接受口服美沙酮维持治疗的稳定患者中，开始每日两次600毫克阿巴卡韦治疗，美沙酮的清除率增加了22%；在大多数患者中，清除率的增加在临床上不会显著；少数患者可能需要增加美沙酮的剂量。

Methadone clearance increased 22% in patients stabilized on oral methadone maintenance therapy who started abacavir therapy with 600 mg twice daily; increase in clearance will not be clinically significant in the majority of patients; methadone dosage increase may be required in a small number of patients.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

基本治疗：建立专利气道。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，协助通气。通过非循环呼吸面罩以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……。预见并处理癫痫发作……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用生理盐水连续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的干呕反射且不流口水，则用水冲洗口腔，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/

Basic treatment: Establish a patent airway. 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 normal saline 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 ... . /Poison A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

高级治疗：对于无意识、严重肺水肿或呼吸停止的患者，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。监测心率和必要时治疗心律失常。 ... 开始静脉输液，使用D5W/SRP：“保持开放”，最低流量/。如果出现低血容量的迹象，使用乳酸钠林格氏液。注意液体过载的迹象。考虑使用药物治疗肺水肿。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象。用地西泮（安定）治疗癫痫。使用丙美卡因氢氯化物协助眼部冲洗。/毒药A和B/

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在口服600毫克放射性阿巴卡韦后，82.2%的剂量通过尿液排出，16%的剂量通过粪便排出。尿液中的5-羧酸代谢物、5-葡萄糖苷酸代谢物和未改变的阿巴卡韦分别占回收放射性活性的30%、36%和1.2%；未识别的次要代谢物占尿液回收放射性活性的15%。

Following oral administration of a 600-mg dose of radiolabeled abacavir, 82.2% of the dose is excreted in urine and 16% of the dose is excreted in feces. The 5-carboxylic acid metabolite, 5-glucuronide metabolite, and unchanged abacavir accounted for 30, 36, and 1.2%, respectively, of recovered radioactivity in urine; unidentified minor metabolites accounted for 15% of recovered radioactivity in urine.