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

中文名称
——
中文别名
——
英文名称
2-[(4R,5S,6S,7R,9R,10R,11E,13Z,16R)-6-[(2S,3R,4R,5S,6R)-5-[(2S,4R,5S,6S)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[(2R,5S,6R)-5-(dimethylamino)-6-methyloxan-2-yl]oxy-4-hydroxy-5-methoxy-9,16-dimethyl-2-oxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde
英文别名
——
2-[(4R,5S,6S,7R,9R,10R,11E,13Z,16R)-6-[(2S,3R,4R,5S,6R)-5-[(2S,4R,5S,6S)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[(2R,5S,6R)-5-(dimethylamino)-6-methyloxan-2-yl]oxy-4-hydroxy-5-methoxy-9,16-dimethyl-2-oxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde化学式
CAS
——
化学式
C43H74N2O14
mdl
——
分子量
843.1
InChiKey
ACTOXUHEUCPTEW-LFIIGWMYSA-N
BEILSTEIN
——
EINECS
——
  • 物化性质
  • 计算性质
  • ADMET
  • 安全信息
  • SDS
  • 制备方法与用途
  • 上下游信息
  • 反应信息
  • 文献信息
  • 表征谱图
  • 同类化合物
  • 相关功能分类
  • 相关结构分类

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,形成了新大环内酯类药物的代谢物——去甲基大环内酯衍生物(neospiramycin)。在给药后14-28天内,肌肉和肾脏中neospiramycin的浓度略高于spiramycin;在肌肉中,neospiramycin和spiramycin的平大约相等。
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在肝脏中被代谢成活性代谢物;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通过其他途径给药。它还被用于治疗原虫感染,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。一名在饲料厂工作的男子由于空气中的螺旋霉素发生了过敏性接触性皮炎。患者在工作期间裸露区域反复出现湿疹性皮损。螺旋霉素还据报道会引起超敏反应。一名34岁的女性在制药厂处理螺旋霉素粉末时出现了鼻炎和刺激性咳嗽。接触药物后几小时内出现症状,并在离开工作场所后持续数小时。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复现了他的症状,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由于螺旋霉素引起的支气管哮喘。这些工人在接触螺旋霉素粉末时会出现咳嗽、呼吸困难和哮喘症状。离开工作3或4天后症状消失。动物研究:每组2只雄性和2只雌性猴子(Macaca fascicularis)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出现了过度流涎。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,给予相当于最高3900 mg/kg bw的剂量,持续13周,注意到的唯一主要效果是一些中剂量和高剂量动物的粒细胞计数减少,以及盲肠扩张。在另一项大鼠饮食研究中,动物被给予相当于最高720 mg/kg bw/day的剂量,持续一年。注意到的唯一显著效果是高剂量雌性动物的体重减轻,以及高剂量平下,两性动物的相对肝、肾和肾上腺重量增加。所有剂量平都发生了肝糖原耗竭,但对照组没有。在给予杂种犬500 mg/kg bw/day,持续最多56天的研究中,观察到精子生成减少和睾丸萎缩。还看到了肾脏损伤。当比格犬口服螺旋霉素,剂量相当于最高150 mg/kg bw/day,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。在小鼠的致畸性研究中,从妊娠第5天到第15天口服螺旋霉素剂量高达400 mg/kg bw,对妊娠结果没有影响。大鼠在妊娠第6天至第15天,兔在妊娠第6天至第19天,静脉注射高达84 mg/kg bw/day的剂量,对发育没有影响,但在兔中,口服200和400 mg/kg bw/day的剂量会导致母兔盲肠增大。在妊娠第6天至第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出现短暂的(5分钟)共济失调和震颤。中间剂量时胎仔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任何胎儿异常的增加。在一项研究中,给雄性大鼠以30 mg/kg bw/day的剂量,通过未指明的途径给药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均得到了阴性结果。
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,并且常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,有多份报告指出大环内酯类药物可能是临床严重药物相互作用的潜在来源。然而,不同的大环内酯类药物在这方面存在差异,并非所有的大环内酯类药物都会引起药物相互作用。随着许多半合成大环内酯类抗生素的近期出现,现在它们可以明显地被分为三组,以引起药物相互作用。第一组(例如脱罗万象素、红霉素)是那些容易形成亚硝基烷的药物,并因此形成不活跃的细胞色素P450-代谢物复合物。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、罗吉红霉素地红霉素阿奇霉素)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的诱导以及体内或体外形成抑制性的细胞色素P450--亚硝基烷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性。脱罗万象素在微粒体肝酶抑制剂中排名第一,导致甲基强的松龙、茶碱、卡马西平非那宗