2-[(4S,5R,6R,7S,9S,10S,11E,13E,16S)-6-[5-(4,5-dihydroxy-4,6-dimethyloxan-2-yl)oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[5-(dimethylamino)-6-methyloxan-2-yl]oxy-4-hydroxy-5-methoxy-9,16-dimethyl-2-oxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde | 8025-81-8

• 物质功能分类: 原料药 - 抗生素类药物
• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-[(4S,5R,6R,7S,9S,10S,11E,13E,16S)-6-[5-(4,5-dihydroxy-4,6-dimethyloxan-2-yl)oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[5-(dimethylamino)-6-methyloxan-2-yl]oxy-4-hydroxy-5-methoxy-9,16-dimethyl-2-oxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde
• CAS: 8025-81-8
• 化学式: C₄₃H₇₄N₂O₁₄
• 分子量: 843.1
• InChiKey: ACTOXUHEUCPTEW-NHYPZVJXSA-N

物化性质

• 熔点：
  126-128 °C
• 沸点：
  914℃
• 比旋光度：
  D20 -80° (methanol)
• 闪点：
  >110°(230°F)
• 溶解度：
  乙醇：50 mg/mL，清澈至微浑浊，淡黄色
• 颜色/状态：
  Amorphous
• 蒸汽压力：
  9.9X10-31 mm Hg at 25 °C (est)
• 亨利常数：
  Henry's Law constant = 9.0X10-35 atm-cu m/mol at 25 °C (est)
• 旋光度：
  Specific optical rotation: -80 deg at 20 °C/D
• 分解：
  When heated to decomposition it emits acrid smoke & irritating fumes.
• 解离常数：
  pKa1 = 7.88; pKa2 = 9.28 (est)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  59
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  195
• 氢给体数：
  4
• 氢受体数：
  16

ADMET

代谢

在牛体内，形成了新斯皮拉霉素这种代谢物，它是脱糖基衍生物。在给药后14-28天，新斯皮拉霉素在肌肉和肾脏中的浓度略高于斯皮拉霉素；在肌肉中，新斯皮拉霉素和斯皮拉霉素的水平大致相等。

In cattle, the metabolite neospiramycin, the demycarosyl derivative, is formed. Concentrations of neospiramycin in muscle and kidney were marginally higher than those of spiramycin 14-28 days after dosing; in muscle, levels of neospiramycin and spiramycin were approximately equal.

来源:Hazardous Substances Data Bank (HSDB)

代谢

spiramycin在肝脏中代谢为活性代谢物；大量通过胆汁排出，约10%通过尿液排出。

Spiramycin is metabolized in the liver to active metabolites; substantial amounts are excreted in the bile and about 10% in the urine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：螺旋霉素是一种大环内酯类抗生素，用于治疗和控制动物中的一些细菌和支原体感染。它以螺旋霉素松酯的形式用于动物饲料，并作为更易溶的螺旋霉素戊酸盐形式用于其他途径的给药。它还用于治疗原虫感染，如隐孢子虫病和弓形虫病。人类暴露和毒性：据报道，螺旋霉素在职业环境中会引起接触性皮炎。一名在饲料工厂工作的男子由于空气中的螺旋霉素而发展成了过敏性接触性皮炎。患者在工作期间未遮盖的区域出现了反复的湿疹性病变。螺旋霉素还报道称会引起过敏反应。一名34岁的女性在制药厂处理螺旋霉素粉末时出现了鼻结膜炎和痉挛性咳嗽。接触药物后几小时内出现症状，并在离开工作地点后持续数小时。一名35岁的非过敏性维护工程师在制药行业工作一年后出现了打喷嚏、咳嗽和呼吸困难的发作。在医院进行的逐渐增加螺旋霉素剂量的吸入挑战测试重现了他的症状，并导致了迟发型哮喘反应的发生。此外，还报告了两例制药厂工人因螺旋霉素引起的支气管哮喘。在工作时接触螺旋霉素粉末时，受试者会出现咳嗽、呼吸困难和哮喘症状。离开工作超过3或4天后症状消失。动物研究：将2只雄性和2只雌性猴子（Macaca fascicularis）每组每天静脉注射0、240,000、360,000和540,000 IU/kg bw的螺旋霉素戊酸盐，持续5天。所有剂量组在注射期间都发生了过度流涎。在几只高剂量猴子和一只低剂量猴子中出现了肌肉张力减退和恶心性痉挛。体重没有异常，但所有处理动物的食物消耗量都有所减少。在高剂量动物中注意到血红蛋白、红细胞数量和血细胞比容略有下降。在一项大鼠短期饮食研究中，给予相当于高达3900 mg/kg bw的剂量，持续13周，注意到的主要影响是一些中剂量和高剂量动物的中性粒细胞计数减少，以及盲肠扩张。在另一项大鼠饮食研究中，动物被给予相当于高达720 mg/kg bw/day的剂量，持续一年。注意到的显著影响是高剂量雌性动物的体重减轻，以及高剂量水平下，两种性别动物的相对肝、肾和肾上腺重量增加。在所有剂量水平下都发生了肝糖原耗竭，但对照组没有。在给予杂种狗500 mg/kg bw/day，持续多达56天的实验中，观察到了精子生成减少和睾丸萎缩。还看到了肾脏损伤。当比格犬口服相当于150 mg/kg bw/day的螺旋霉素，持续两年时，没有看到睾丸损伤，尽管其他器官发生了退行性变化。在针对小鼠的致畸性研究中，在妊娠的第5-15天口服高达400 mg/kg bw的螺旋霉素对妊娠结果没有影响。在大鼠妊娠的第6-15天和兔子的第6-19天，静脉注射高达84 mg/kg bw/day的剂量对发育没有影响，但在兔子中口服200和400 mg/kg bw/day的剂量导致了母体盲肠增大。在妊娠的第6-15天，将20只怀孕大鼠静脉注射0、90,000、180,000和270,000 IU/kg bw/day的螺旋霉素戊酸盐。最高剂量给药后立即产生了短暂的（5分钟）共济失调和震颤。在中间剂量下，胎儿体重略有但显著降低，但所有值都在历史对照范围内。在这项研究中没有注意到胎儿异常的发生率增加。在一项研究中，给予雄性大鼠30 mg/kg bw/day的剂量，通过未指明的途径持续8天，注意到了精原细胞的有丝分裂和减数分裂异常。在体外哺乳动物细胞正向突变试验、体外细胞遗传学分析和小鼠微核试验中，螺旋霉素戊酸盐和螺旋霉素松酯得到了阴性结果。

IDENTIFICATION AND USE: Spiramycin is a macrolide antibiotic used for the treatment and control of a number of bacterial and mycoplasmal infections in animals. It is available as a spiramycin embonate for use in animal feed, and as the adipate, a more soluble form, for administration by other routes. It has also been used in the protozoal infections cryptosporidiosis and toxoplasmosis. HUMAN EXPOSURE AND TOXICITY: Spiramycin is reported to cause contact dermatitis in occupational settings. A man who worked in a feed factory developed allergic contact dermatitis due to airborne spiramycin. The patient suffered recurrent outbreaks of eczematous lesions on uncovered areas during working periods. Spiramycin is also reported to cause hypersensitivity reactions. Rhinoconjunctivitis and spasmodic cough are reported in a 34 year-old female handling spiramycin powder in a pharmaceutical factory. The symptoms appeared within the first few hours of coming into contact with the drug and continued for several hours after leaving her place of work. One year after starting work in the pharmaceutical industry a 35-year-old non-atopic maintenance engineer developed attacks of sneezing, coughing and breathlessness. Inhalation challenge tests carried out in the hospital with gradually increasing quantities of spiramycin reproduced his symptoms and led to the development of late asthmatic reactions. Additionally, two cases of bronchial asthma due to spiramycin in workers of a pharmaceutical factory were reported. The subjects complained of cough, breathlessness and symptoms of asthma at work when coming into contact with spiramycin's powder. The symptoms cleared when away from work for more than 3 or 4 days. ANIMAL STUDIES: Groups of 2 male and 2 female monkeys (Macaca fascicularis) were given daily intravenous injections of 0, 240,000, 360,000, and 540,000 iu/kg bw/day spiramycin adipate for 5 days. Hypersalivation occurred during injection in all dose groups. Muscle hypotonia and nauseous spasticity occurred in several high dose monkeys and in one given the low dose. No abnormalities of body weights occurred but food consumption was reduced in all treated animals. A slight decrease in hemoglobin, red cell numbers and hematocrit was noted in high dose animals. In a short-term dietary study in which rats were given the equivalent of up to 3900 mg/kg bw for 13 weeks, the only major effects noted were a reduction in neutrophil counts in some mid- and high-dose animals, and the dilatation of the caecum. In another dietary study in the rat, animals were given up to the equivalent of 720 mg/kg bw/day for one year. The only notable effects were reductions in the body weights of females receiving the high doses, and increases in relative liver, kidney, and adrenal weights at high dose levels in animals of both sexes. Hepatic glycogen depletion occurred at all dose levels but not in controls. In mongrel dogs given 500 mg/kg bw/day for up to 56 days, reductions in spermatogenesis and testicular atrophy occurred. Kidney damage was also seen. When beagles were given orally spiramycin at up to the equivalent of 150 mg/kg bw/day for two years, testicular damage was not seen although degenerative changes occurred in other organs. In teratogenicity studies in mice, oral doses of spiramycin of up to 400 mg/kg bw given over days 5-15 of gestation had no effects on the outcome of pregnancy. intravenous doses of up to 84 mg/kg bw/day given on days 6-15 of gestation to rats and day 6-19 to rabbits had no effect on developmental, but oral dose of 200 and 400 mg/kg bw/day in rabbit produced caecal enlargement in mothers. Groups of 20 pregnant rats were treated intravenously on days 6-15 of gestation with doses of 0, 90 000, 180 000, and 270 000 iu/kg bw/day with spiramycin adipate. The highest dose given produced brief (5 minutes) ataxia and tremors immediately after dosing. A slight but significant reduction in fetal weight occurred at the intermediate dose but all values were within historical control ranges. There were no increased incidences of any fetal anomaly noted in this study. In a study where male rats were given doses of 30 mg/kg bw/day for 8 days by an unspecified route, mitotic and meiotic abnormalities in spermatogonia were noted. Negative result were obtained with spiramycin adipate and embonate in a forward-mutation test in mammalian cells in vitro, in an in vitro cytogenic assay, and in the mouse micronucleus test.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

大环内酯类抗生素包括天然成员、前药和半合成衍生物。这些药物适用于多种感染，并经常与其他药物疗法联合使用，因此存在产生药物动力学相互作用的潜在风险。大环内酯类药物可以通过形成复合物并使微粒体药物氧化酶失活来抑制肝脏中的药物代谢，同时通过其抗生素效果干扰肠内微生物群。在过去20年中，有多份报告指责大环内酯类抗生素是严重药物相互作用的潜在来源。然而，不同的大环内酯类抗生素在这方面存在差异，并非所有的大环内酯类都会导致药物相互作用。随着许多半合成大环内酯类抗生素的最近出现，现在可以明确的是，它们可能导致药物相互作用的三个不同类别。第一组（例如多里环素、红霉素）是那些容易形成亚硝基烷烃并因此形成无活性的细胞色素P450-代谢物复合物的药物。第二组（例如约沙霉素、氟红霉素、罗红霉素、克拉霉素、米卡霉素和米地卡霉素）形成复合物的程度较小，很少产生药物相互作用。最后一组（例如螺旋霉素、罗吉他霉素、地红霉素和阿奇霉素）不会使细胞色素P450失活，也无法改变其他化合物的药物动力学。似乎有两个结构因素对于大环内酯类抗生素导致细胞色素P450的诱导以及在体内或体外形成抑制性的细胞色素P450-铁-亚硝基烷烃代谢物复合物至关重要：大环内酯分子中存在一个非阻碍性的、易于接近的N-二甲氨基团以及药物的疏水性特征。多里环素是最强的微粒体肝酶抑制剂，能显著减少甲基强的松龙、茶碱、卡马西平、非那宗（安替比林）和三唑仑的代谢。多里环素可能导致服用麦角生物碱的患者出现麦角病，以及那些服用口服避孕药的患者出现胆汁淤积性黄疸。红霉素及其不同的前药似乎是对药物代谢的较不强烈抑制剂。然而，病例报告和控制研究已经表明，红霉素可能会与茶碱、卡马西平、甲基强的松龙、华法林、环孢素、三唑仑、咪达唑仑、阿芬太尼、双异丙吡胺和溴隐亭发生相互作用，降低药物清除率。红霉素似乎也能增加那些排泄大量还原型地高辛代谢物患者的地高辛的生物利用度，这可能是由于破坏了负责形成这些化合物的肠内菌群。这些被