(1S,2R,18R,19R,22S,25R,28R,40S)-48-[(2S,3S,5S)-3-[(2S,4R,5R)-4-amino-5-hydroxy-4,6-dimethyloxan-2-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-22-(2-amino-2-oxoethyl)-5,15-dichloro-2,18,32,35,37-pentahydroxy-19-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentazaoctacyclo[26.14.2.23,6.214,17.18,12.129,33.010,25.034,39]pentaconta-3,5,8(48),9,11,14,16,29(45),30,32,34(39),35,37,46,49-pentadecaene-40-carboxylic acid;hydrochloride

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (1S,2R,18R,19R,22S,25R,28R,40S)-48-[(2S,3S,5S)-3-[(2S,4R,5R)-4-amino-5-hydroxy-4,6-dimethyloxan-2-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-22-(2-amino-2-oxoethyl)-5,15-dichloro-2,18,32,35,37-pentahydroxy-19-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentazaoctacyclo[26.14.2.23,6.214,17.18,12.129,33.010,25.034,39]pentaconta-3,5,8(48),9,11,14,16,29(45),30,32,34(39),35,37,46,49-pentadecaene-40-carboxylic acid;hydrochloride
• 化学式: C66H76Cl3N9O24
• 分子量: 1485.7
• InChiKey: LCTORFDMHNKUSG-MPBVRSTOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.53
• 重原子数：
  102
• 可旋转键数：
  13
• 环数：
  12.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  531
• 氢给体数：
  20
• 氢受体数：
  26

ADMET

毒理性

• 肝毒性

静脉注射万古霉素与1%至5%的患者血清转氨酶水平轻微、短暂和无症状升高有关，但与此相比，类似或略低的异常率通常与其他比较药物相关。在罕见的情况下，血清酶水平的升高更为明显，并可能伴有轻度症状，尽管通常没有黄疸。近年来，万古霉素与过敏反应有关，包括史蒂文斯-约翰逊综合征、中毒性表皮坏死松解症和药物反应、嗜酸性粒细胞增多和系统性症状（DRESS）的独特综合征。这些过敏反应通常在开始静脉注射（iv）万古霉素治疗后的几天到3到4周内出现。发热和严重的皮疹通常主导着临床表现，但系统性症状可能包括肾脏、呼吸或心脏衰竭、中性粒细胞减少、血小板减少和肝脏损伤。与万古霉素相关的DRESS综合征的病例通常伴有血清酶水平升高（案例1），但显著升高、症状和黄疸并不常见。万古霉素诱导的DRESS综合征的典型系统性特征是肾脏而非肝脏损伤，但过敏反应的特征通常比器官特异性损伤更为突出。然而，在罕见的情况下，肝脏损伤可能很严重（案例2），并可能导致肝衰竭和死亡。接受静脉注射万古霉素的患者通常有多种并存疾病，包括败血症，并接受多种抗生素，这使得将过敏反应和肝脏损伤归因于万古霉素变得困难。其他更知名的DRESS综合征的原因包括别嘌呤醇、磺胺类药物和芳香抗惊厥药。这些DRESS综合征的其他原因更有可能与临床上明显的甚至致命的肝脏损伤有关。 万古霉素也与几种急性输注反应有关，尤其是过敏性休克和万古霉素潮红反应，以前被称为“红人综合征”。万古霉素潮红反应通常发生在初次输注万古霉素的前15到20分钟，尤其是在快速给药和高剂量（1000毫克在不到60分钟内给药）时。这种反应的特点是潮红、红斑和通常发生在面部、颈部和上半身的瘙痒，有时伴有胸痛和背痛以及不同程度的低血压。罕见的是，潮红反应与口服万古霉素治疗有关，特别是在患有活动性结肠炎和肾功能障碍的老年患者中。症状的原因可能是万古霉素或金黄色葡萄球菌毒素直接作用于肥大细胞的急性脱颗粒。这种反应的介质是组胺和其他活性胺或肥大细胞颗粒中的成分。万古霉素潮红反应的人的血浆组胺水平通常升高，但血浆组胺水平的变化与症状严重性的相关性较差。然而，通过预先使用抗组胺药可以预防或减轻万古霉素潮红反应的症状。也许更好的方法是使用更慢的输注速率和较低的万古霉素剂量。肝脏损伤不是万古霉素潮红反应的特征，但在持续或严重低血压的情况下可能会继发出现。 可能性评分：B（通常是临床上明显肝脏损伤的高度可能原因，通常与DRESS综合征有关）。

Intravenous vancomycin is associated with minor, transient and asymptomatic elevations in serum aminotransferase levels in 1% to 5% of patients, but similar or minimally lower rates of abnormalities are usually reported with comparative agents. In rare instances, the serum enzyme elevations are more marked and may be associated with mild symptoms, although usually without jaundice. In recent years, vancomycin has been linked to hypersensitivity reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and the distinctive syndrome of drug reaction, eosinophilia and systemic symptoms (DRESS). These forms of hypersensitivity generally arise within a few days to 3 to 4 weeks after initiation of intravenous (iv) vancomycin therapy. Fever and severe skin rash generally dominate the clinical presentation, but systemic symptoms can include renal, respiratory or heart failure, neutropenia, thrombocytopenia, and liver injury. Cases of DRESS syndrome associated with vancomycin are often accompanied by serum enzyme elevations (Case 1), but marked elevations, symptoms and jaundice are uncommon. The usual systemic features of vancomycin induced DRESS syndrome are renal rather than liver injury but features of hypersensitivity are usually more prominent than organ-specific injury. Nevertheless, in rare instances the liver injury can be severe (Case 2) and result in hepatic failure and death. Patients who receive intravenous vancomycin often have multiple comorbidities including sepsis and receive multiple antibiotics which make the attribution of the hypersensitivity reactions and liver injury with vancomycin difficult. Other more well-known causes of DRESS syndrome include allopurinol, sulfonamides, and the aromatic anticonvulsants. These other causes of DRESS syndrome are more likely to be associated with clinically apparent and even fatal liver injury. Vancomycin is also associated with several forms of acute infusion reactions, most notably anaphylaxis and the vancomycin flushing reaction, previously known as “red man syndrome”. Vancomycin flushing reactions occur typically during the first 15 to 20 minutes of an initial infusion of vancomycin, most commonly when given rapidly and in relative high doses (1000 mg given over less than 60 minutes). The reaction is characterized by flushing, erythema, and itching usually of the face, neck and upper torso, sometimes accompanied by chest and back pain and variable degrees of hypotension. Rarely, flushing reactions have been associated with oral vancomycin therapy, particularly in elderly patients with active colitis and renal dysfunction. The cause of the symptoms is probably the acute degranulation of mast cells by the direct effect of vancomycin or S. Aureus toxins. The mediator of the reaction is histamine and other active amines or components in mast cell granules. Plasma histamine levels are usually elevated in persons with vancomycin flushing reactions, but the correlation of changes in plasma histamine levels and severity of symptoms is poor. Nevertheless, the symptoms of the vancomycin flushing reaction can be prevented or ameliorated by pretreatment with antihistamines. Perhaps a better approach is the use of slower infusion rates and lower doses of vancomycin. Liver injury is not a feature of vancomycin flushing reactions but can arise secondarily in cases with prolonged or severe hypotension. Likelihood score: B (highly likely cause of clinically apparent liver injury usually in association with DRESS syndrome).

来源:LiverTox