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2-[(4R,5S,6S,7S,9R,11E,13E,15R,16R)-6-[(3R,5S)-5-[(2S,5S,6S)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-16-ethyl-4-hydroxy-15-[[(2R,3S,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl]oxymethyl]-5,9,13-trimethyl-2,10-dioxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde | 1401-69-0

中文名称
——
中文别名
——
英文名称
2-[(4R,5S,6S,7S,9R,11E,13E,15R,16R)-6-[(3R,5S)-5-[(2S,5S,6S)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-16-ethyl-4-hydroxy-15-[[(2R,3S,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl]oxymethyl]-5,9,13-trimethyl-2,10-dioxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde
英文别名
——
2-[(4R,5S,6S,7S,9R,11E,13E,15R,16R)-6-[(3R,5S)-5-[(2S,5S,6S)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-16-ethyl-4-hydroxy-15-[[(2R,3S,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl]oxymethyl]-5,9,13-trimethyl-2,10-dioxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde化学式
CAS
1401-69-0
化学式
C46H77NO17
mdl
——
分子量
916.1
InChiKey
WBPYTXDJUQJLPQ-ZAXAODHASA-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

物化性质

  • 熔点:
    135-137°C
  • 比旋光度:
    D25 -46° (c = 2 in methanol)
  • 沸点:
    796.05°C (rough estimate)
  • 密度:
    1.1424 (rough estimate)
  • 溶解度:
    DMF:30mg/mL; DMSO:25mg/mL;乙醇:30mg/mL
  • 颜色/状态:
    Crystals from water
  • 蒸汽压力:
    1.98X10-34 mm Hg at 25 °C (est)
  • 稳定性/保质期:
    Stable under recommended storage conditions.
  • 旋光度:
    Specific optical rotation: -46 deg at 25 °C/D (c = 2 cm methanol)
  • 分解:
    When heated to decomposition it emits toxic fumes of /nitrogen oxide/.
  • 解离常数:
    pKa = 7.73

计算性质

  • 辛醇/水分配系数(LogP):
    1
  • 重原子数:
    64
  • 可旋转键数:
    13
  • 环数:
    4.0
  • sp3杂化的碳原子比例:
    0.85
  • 拓扑面积:
    239
  • 氢给体数:
    5
  • 氢受体数:
    18

ADMET

代谢
链霉菌属弗拉德菌的泰乐菌素生物合成(tyl)基因簇包含辅助基因,这些基因编码通常与初级代谢相关的功能。这些基因的破坏不会导致生存能力的丧失,因为基因组其他位置也存在着等效基因(可能用于“看家”目的)。tyl簇还包含两个编码与数据库中任何蛋白质都不同的产物的基因。两个辅助基因,metF(编码N5,N10-亚甲基四氢叶酸还原酶)和metK(编码S-腺苷甲硫氨酸合成酶),位于tyl簇中的一个“未知”基因(orf9)的两侧。在所有这三个基因都被破坏的弗拉德菌菌株中,泰乐菌素的产量降低了,尽管这种效果在补充了甘氨酸甜菜碱的培养基中被掩盖了,因为甘氨酸甜菜碱可以向四氢叶酸池提供甲基。显然,将辅助基因招募到tyl簇的一个后果是增强了次级代谢期间转甲基的能力。
The tylosin-biosynthetic (tyl) gene cluster of Streptomyces fradiae contains ancillary genes that encode functions normally associated with primary metabolism. These can be disrupted without loss of viability, since equivalent genes (presumably used for 'housekeeping' purposes) are also present elsewhere in the genome. The tyl cluster also contains two genes that encode products unlike any proteins in the databases. Two ancillary genes, metF (encoding N5,N10-methylenetetrahydrofolate reductase) and metK, encoding S-adenosylmethionine synthase, flank one of the 'unknown' genes (orf9) in the tyl cluster. In a strain of S. fradiae in which all three of these genes were disrupted, tylosin production was reduced, although this effect was obscured in media supplemented with glycine betaine which can donate methyl groups to the tetrahydrofolate pool. Apparently, one consequence of the recruitment of ancillary genes into the tyl cluster is enhanced capacity for transmethylation during secondary metabolism.
来源:Hazardous Substances Data Bank (HSDB)
代谢
关于致病性诺卡氏菌对大环内酯类抗生素(沙链霉素和泰乐菌素)的敏感性研究显示,大多数被检测的诺卡氏菌种类对这两种抗生素都有很高的耐药性,尽管N. nova(诺卡氏菌属的一个种)对此有一定的敏感性。N. asteroides IFM 0339(一种诺卡氏菌)通过在2'-OH位的糖基化或糖基化并还原20位的甲酰基团,将这些大环内酯类抗生素转化为无活性的代谢物。通过核磁共振(NMR)和质谱(MS)数据确定了代谢物的结构,分别为2'-[O-(beta-D-吡喃葡萄糖基)]沙链霉素(2),2'-[O-(beta-D-吡喃葡萄糖基)]泰乐菌素(5)和20-二氢-2'-[O-(beta-D-吡喃葡萄糖基)]泰乐菌素(4)。
Studies on the susceptibility of pathogenic Nocardia to macrolide antibiotics, chalcomycin and tylosin, showed that most of the Nocardia species examined were highly resistant to both antibiotics, although N. nova was moderately susceptible. N. asteroides IFM 0339 converted these macrolides into inactive metabolites by glycosylation at 2'-OH or glycosylation and reduction of the 20-formyl group. The structures of the metabolites were determined from NMR and MS data to be 2'-[O-(beta-D-glucopyranosyl)]chalcomycin (2), 2'-[O-(beta-D-glucopyranosyl)]tylosin (5) and 20-dihydro-2'-[O-(beta-D-glucopyranosyl)]tylosin (4).
来源:Hazardous Substances Data Bank (HSDB)
代谢
泰乐菌素是由 Streptomyces fradiae 通过聚酮代谢和三种脱氧己糖的合成相结合产生的,其中mycaminose是最先添加到聚酮苷元tylactone(原泰乐菌素)的。以前,破坏编码mycaminose与苷元连接的基因(tylMII)意外地消除了后者的积累,这提高了在S. fradiae中聚酮代谢与脱氧己糖生物合成之间存在联系的可能性。然而,当时,无法排除另一种解释,即对不参与mycaminose代谢的其他基因表达产生下游影响可能导致了这种现象。在这里,研究表明破坏四个特定参与mycaminose生物合成的基因(tylMI-III和tylB)中的任何一个都会引起类似的反应,这证实了mycaminosyl-tylactone的产生直接影响S. fradiae中的聚酮代谢。在类似条件下,当mycaminose生物合成被基因破坏特异性阻断时,通过外源添加糖基化的泰乐菌素前体可以恢复tylactone的积累。此外,还发现某些非泰乐菌素途径的其他大环内酯也具有定性相似的效应。比较刺激性的大环内酯的结构将有助于研究刺激机制。
Tylosin is produced by Streptomyces fradiae via a combination of polyketide metabolism and synthesis of three deoxyhexose sugars, of which mycaminose is the first to be added to the polyketide aglycone, tylactone (protylonolide). Previously, disruption of the gene (tylMII) encoding attachment of mycaminose to the aglycone unexpectedly abolished accumulation of the latter, raising the possibility of a link between polyketide metabolism and deoxyhexose biosynthesis in S. fradiae. However, at that time, it was not possible to eliminate an alternative explanation, namely, that downstream effects on the expression of other genes, not involved in mycaminose metabolism, might have contributed to this phenomenon. Here, it is shown that disruption of any of the four genes (tylMI--III and tylB) specifically involved in mycaminose biosynthesis elicits a similar response, confirming that production of mycaminosyl-tylactone directly influences polyketide metabolism in S. fradiae. Under similar conditions, when mycaminose biosynthesis was specifically blocked by gene disruption, accumulation of tylactone could be restored by exogenous addition of glycosylated tylosin precursors. Moreover, certain other macrolides, not of the tylosin pathway, were also found to elicit qualitatively similar effects. Comparison of the structures of stimulatory macrolides will facilitate studies of the stimulatory mechanism.
来源:Hazardous Substances Data Bank (HSDB)
代谢
在链霉菌属的弗拉德链霉菌中,参与泰乐菌素生物合成的有三个糖基转移酶。首先添加到多酮类化合物苷元(泰乳菌素)上的糖是麦卡米糖,编码麦卡米糖基转移酶的基因是orf2*(tylM2)。然而,定向破坏orf2*并没有导致在通常有利于泰乐菌素生产的条件下泰乳菌素的积累;相反,泰乳菌素的合成实际上被完全取消了。这部分可能是因为对orf2*下游基因表达的影响,尤其是orf4*(ccr),它编码肉桂酰辅酶A还原酶,这是一种为多酮类代谢提供4碳延伸单元的酶。然而,这并不能完全解释现象,因为当orf2*被重新引入到破坏的菌株中时,泰乐菌素的生产恢复了大约野生型水平的10%。当将泰乐菌素的糖基化前体喂给破坏的菌株时,它们被转化为泰乐菌素,确认了与泰乐菌素生物合成相关的三个糖基转移酶中有两个仍然完整。然而,有趣的是,在这种条件下泰乳菌素也积累了,而当泰乐菌素被添加到类似的发酵中时,积累的程度要小得多。因此,得出结论,糖基化的麦罗菌素对弗拉德链霉菌中的多酮类代谢产生了明显的正向影响。
Three glycosyltransferases are involved in tylosin biosynthesis in Streptomyces fradiae. The first sugar to be added to the polyketide aglycone (tylactone) is mycaminose and the gene encoding mycaminosyltransferase is orf2* (tylM2). However, targeted disruption of orf2* did not lead to the accumulation of tylactone under conditions that normally favor tylosin production; instead, the synthesis of tylactone was virtually abolished. This may, in part, have resulted from a polar effect on the expression of genes downstream of orf2*, particularly orf4* (ccr) which encodes crotonyl-CoA reductase, an enzyme that supplies 4-carbon extender units for polyketide metabolism. However, that cannot be the entire explanation, since tylosin production was restored at about 10% of the wild-type level when orf2* was re-introduced into the disrupted strain. When glycosylated precursors of tylosin were fed to the disrupted strain, they were converted to tylosin, confirming that two of the three glycosyltransferase activities associated with tylosin biosynthesis were still intact. Interestingly, however, tylactone also accumulated under such conditions and, to a much lesser extent, when tylosin was added to similar fermentations. It is concluded that glycosylated macrolides exert a pronounced positive effect on polyketide metabolism in S. fradiae.
来源:Hazardous Substances Data Bank (HSDB)
代谢
Fischer 344 大鼠每天口服剂量为 10 毫克每千克体重的 (14)C-泰乐菌素,持续 4 天。每天收集尿液和粪便。大约 95% 的放射性物质在粪便中找到。最后一次给药后 4 小时处死大鼠,此时肝脏的平均放射性浓度为 0.09 毫克当量每千克。放射性物质的分离表明肝脏中存在多种代谢物,包括泰乐菌素 A、利洛霉素、二氢去甲麦角菌素和半胱氨酰泰乐菌素 A,尽管后者的证据并不确凿。粪便中的主要成分为利洛霉素(24%)和二氢去甲麦角菌素(11%)。粪便中的次要成分包括泰乐菌素 A、麦卡霉素、泰乐菌素 A 的内酯酸、利洛霉素的内酯酸和去甲基二氢去甲麦角菌素。内酯酸是大环内酯环中内酯水解的产物。
Fischer 344 rats were given oral doses of 10 mg (14)C-tylosin/kg bw per day for 4 days. Urine and faeces were collected daily. Approximately 95% of the excreted radioactivity was found in feces. The rats were euthanized 4 hr after the last dose, when the liver had a mean radioactivity concentration of 0.09 mg equivalents/kg. Fractionation of radioactivity indicated the presence of multiple metabolites in liver, including tylosin A, relomycin, dihydrodesmycosin and cysteinyltylosin A, although evidence for the latter was not conclusive. The faeces contained relomycin (24%) and dihydrodesmycosin (11%) as the major components. Minor components in the faeces included tylosin A, macrocin, the seco acid of tylosin A, the seco acid of relomycin and desmethyl dihydrodesmycosin. The seco acids are products of hydrolysis of the lactone in the macrolide ring.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 相互作用
在肉鸡中研究了膨润土与泰乐菌素之间的相互作用,基于体内获得的药代动力学特征。同时口服膨润土和泰乐菌素显著降低了泰乐菌素的血浆水平,减少了血浆浓度-时间曲线下的面积(AUC(0-∞))、最大血浆浓度(C(max))、达到最大血浆浓度的时间(T(max))和相对口服生物利用度。结果明确证明了泰乐菌素与膨润土的结合。因此,应避免同时给予泰乐菌素(在饮用水或饲料中)和膨润土(作为霉菌毒素吸附剂混合在饲料中)。
The interaction between bentonite and tylosin was investigated in broiler chickens, based on pharmacokinetic characteristics obtained in vivo. Simultaneous oral administration of bentonite and tylosin significantly lowered plasma levels of tylosin and reduced the area under the plasma concentration-time curve (AUC(0-inf)), maximal plasma concentration (C(max)), time to maximal plasma concentration (T(max)) and relative oral bioavailability. The results prove unambiguously the binding of tylosin by bentonite. Simultaneous administration of tylosin (in the drinking water or feed) and bentonite (mixed in the feed as a mycotoxin binder) should therefore be avoided.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 相互作用
在人身上,一些大环内酯类抗生素通过形成稳定的代谢中间体(MI)复合物与细胞色素P4503A(CYP3A)亚家族的酶发生临床相关的药物-药物相互作用。这种复合物的形成可能导致同时给药的药物的生物转化率降低。在以前的研究中,发现兽用抗生素替米考星也能在猪和 rats 中形成稳定的MI复合物。在目前的研究中,研究了一系列大环内酯类抗生素和替米考星在山羊和牛的微粒体组分以及表达牛CYP3A的细胞系中的CYP3A相对抑制活性和MI复合物形成。发现替米考星和三乙酰奥莱andomycin(TAO)是所有测试系统中的有效CYP450活性抑制剂。红霉素和tilmicosin被发现是相对较弱的CYP450活性抑制剂,在微粒体中,它们在表达牛CYP3A4的细胞系中的活性相对较弱。泰乐菌素在微粒体中显示出是弱抑制剂,在细胞系中则不是,而螺旋霉素根本没有效果。通过光谱分析测量的MI复合物形成发生在TAO、替米考星、红霉素和泰乐菌素上,但tilmicosin和螺旋霉素则没有。尽管在体内还有其他因素发挥作用,但这些结果可能解释了潜在的药物-药物相互作用以及在这方面相关化合物之间的差异。
In humans, clinically relevant drug-drug interactions occur with some macrolide antibiotics via the formation of stable metabolic intermediate (MI) complexes with enzymes of the cytochrome P4503A (CYP3A) subfamily. The formation of such complexes can result in a decreased biotransformation rate of simultaneously administered drugs. In previous studies it was shown that the veterinary antibiotic tiamulin was also able to form a stable MI complex in pigs and rats. In the present study the relative CYP3A inhibiting potency and MI complex formation of a series of macrolide antibiotics and tiamulin were studied in microsomal fractions of goat and cattle and in a cell-line expressing bovine CYP3A. Tiamulin and triacetyloleandomycin (TAO) were found to be effective inhibitors of CYP450 activity in all systems tested. Erythromycin and tilmicosin were found to be relatively less effective inhibitors of CYP450 activity in microsomes, and their activity in the bovine CYP3A4 expressing cell line was relatively weak. Tylosin was shown to be a weak inhibitor in microsomes and not in the cell line, whereas spiramycin had no effect at all. MI-complex formation measured by spectral analysis was seen with TAO, tiamulin, erythromycin and tylosin, but not with tilmicosin and spiramycin. Although additional factors play a role in vivo, these results may explain potential drug-drug interactions and differences between related compounds in this respect.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 毒性总结
鉴定和使用:泰乐菌素用于辅助治疗与鸡败血支原体相关的慢性呼吸道疾病。它也用于减少与火鸡败血支原体相关的传染性鼻窦炎的严重程度。在蜜蜂中,它用于控制美洲幼虫腐臭病(幼虫芽孢杆菌)。最后,泰乐菌素用于治疗和控制与猪螺旋体相关的猪痢疾。人类接触和毒性:农场工人和从事兽医医学的人报告了由泰乐菌素引起的接触性皮炎。动物研究:将泰乐菌素0.1毫升、52毫克或58毫克的Tylan 200注射液、泰乐菌素浓缩液或Tylan可溶性液分别放入兔子的一个眼睛中。Tylan 200注射液引起了非常轻微的结膜充血,在48小时内清除。泰乐菌素浓缩液在接触后1小时内引起了角膜混浊、轻微的角膜混浊、轻至中度的虹膜炎和中度的结膜炎。然而,所有刺激在14天内清除。Tylan可溶性液在1小时内引起了轻至中度的角膜混浊、明显的虹膜炎和中度的结膜炎。在这项研究中,所有刺激在接触后7天内清除。雌性大鼠皮下注射泰乐菌素,剂量高达每天100毫克/千克体重,持续28天,没有毒理学影响。雄性和雌性大鼠在饮食中给予泰乐菌素碱,剂量为0、1000、5000和10000毫克/千克,持续1年。处理的大鼠在测试的7到12个月内表现出中度过度敏感和过度活跃,但没有因处理而导致的死亡。在给予5000和10000毫克/千克饮食的雌性中观察到淋巴细胞数量增加、中性粒细胞数量减少和尿液pH增加。显微镜检查显示,所有处理组的雌性垂体肿瘤略有增加:0、1000、5000和10000毫克/千克饮食分别为1、3、4和3个腺瘤,0、0、1和0个癌。在另一项大鼠研究中,雄性和雌性大鼠被喂食含有0、20000、50000、100000或200000毫克/千克饮食的泰乐菌素碱,持续2年。在两个最高剂量下,体重增加和食物摄入量减少。所有高剂量的大鼠在12个月内死亡,表现出高营养不良、淋巴器官萎缩/坏死的发病率。在一项为期2年的研究中,狗和混合品种的狗通过胶囊口服剂量为0、1、10或100毫克/千克体重/天的泰乐菌素碱。在研究进行153天后,通过添加更多剂量的雄性和雌性杂种狗(每天200或400毫克/千克体重)来扩展研究期。偶尔出现腹泻和呕吐的狗给予10-400毫克/千克体重/天。在两只狗在100毫克/千克体重/天和一只狗在400毫克/千克体重/天记录了暂时升高的溴磺酚酞保留时间。在尸检中,发现一只给予200毫克/千克体重/天的狗有轻度肾盂肾炎,一只给予400毫克/千克体重/天的狗有双侧肾病、轻度慢性肾盂肾炎和轻度慢性膀胱炎。泰乐菌素碱通过灌胃给予小鼠,剂量为0、100、500或1000毫克/千克体重/天,在妊娠的第7-12天。每组给予0或500毫克/千克体重/天的4只小鼠被允许分娩,其余在妊娠第18天被杀死。母体体重增加或胎儿发育没有处理相关的差异。在7周和9周的交付后代中没有发现不良影响。雌性大鼠在妊娠的第0-20天给予含有0、1000、10000或100000毫克/千克饮食的泰乐菌素碱,并在妊娠第20天杀死。在100000毫克/千克饮食中,母体和胎儿的体重下降,骨骼形成延迟。来自对照组和两个最高剂量组的部分雌性从妊娠第0天到出生后第21天进行处理并允许分娩。在100000毫克/千克饮食中,后代体重增加较低。泰乐菌素在小鼠淋巴瘤细胞的体外基因突变诱导试验中呈阳性,但在HGPRT+中国仓鼠卵巢细胞的体外基因突变诱导试验、中国仓鼠卵巢细胞的体外染色体损伤试验和体内小鼠骨髓的细胞遗传学损伤试验中呈阴性。生态毒理学研究:泰乐菌素对调查的淡水绿藻在72小时暴露期内有毒。
IDENTIFICATION AND USE: Tylosin is used as an aid in the treatment of chronic respiratory disease associated with Mycoplasma gallisepticum in chickens. It is also used for the reduction in severity of effects of infectious sinusitis associated with Mycoplasma gallisepticum in turkeys. In honey bees, it is used for the control of American Foulbrood (Paenibacillus larvae). Finally, tylosin is used for the treatment and control of swine dysentery associated with Brachyspira hyodysenteriae. HUMAN EXPOSURE AND TOXICITY: Contact dermatitis caused by tylosin has been reported by farm workers and individuals employed in veterinary medicine. ANIMAL STUDIES: Tylosin was placed in one eye of rabbits in an amount of 0.1 mL, 52 mg or 58 mg of Tylan 200 Injection, Tylosin Concentrate or Tylan Soluble, respectively. Tylan 200 Injection caused very slight conjunctival hyperemia, which cleared within 48 hr. Tylosin Concentrate caused corneal dullness, slight corneal opacity, slight to moderate iritis and moderate conjunctivitis within 1 hr post-exposure. However, all irritation cleared within 14 days. Tylan Soluble caused slight to moderate corneal opacity, marked iritis and moderate conjunctivitis within 1 hr. In this study, all irritation cleared within 7 days post exposure. Female rats were treated subcutaneously with tylosin up to 100 mg/kg bw per day for 28 days without any toxicological effects. Male and female rats were administered tylosin base in the diet for 1 year at levels of 0, 1000, 5000 and 10,000 mg/kg. Treated rats appeared moderately hyperirritable and hyperactive from 7 to 12 months on test, but there was no mortality attributable to treatment. Increased numbers of lymphocytes, decreased numbers of neutrophils and increased urine pH were observed in females given 5000 and 10,000 mg/kg diet. Microscopic examination revealed a slight increase in pituitary tumors in females of all treated groups: 1, 3, 4 and 3 adenomas and 0, 0, 1 and 0 carcinomas at 0, 1000, 5000 and 10,000 mg/kg diet, respectively. In another rat study, male and female rats were fed diets containing 0, 20,000, 50,000, 100,000 or 200,000 mg tylosin base/kg diet for 2 years. Body weight gain and food intake were reduced at the two highest doses. All high-dose rats died within 12 months and exhibited high incidences of malnutrition and atrophy/necrosis of lymphoid organs. In a 2-year study, dogs and mixed-breed dogs were given oral doses of 0, 1, 10 or 100 mg tylosin base/kg bw per day by capsule. After this study had progressed for 153 days, it was expanded by adding further groups of male and female mongrel dogs given doses of 200 or 400 mg tylosin base/kg bw per day for the remainder of the study period. Occasional diarrhea and vomiting occurred in dogs given 10-400 mg/kg bw per day. Transient elevated bromosulfophthalein retention times were recorded in two dogs at 100 mg/kg bw per day and one dog at 400 mg/kg bw per day. At necropsy, mild pyelonephritis was found in one dog given 200 mg/kg bw per day, and bilateral nephrosis, mild chronic pyelonephritis and mild chronic cystitis were seen in one dog given 400 mg/kg bw per day. Tylosin base was given by gavage to mice at doses of 0, 100, 500 or 1000 mg/kg bw per day on gestation days 7-12. Four mice per group given 0 or 500 mg/kg bw per day were allowed to deliver, the remainder were killed on gestation day 18. There were no treatment-related differences in maternal body weight gains or development of fetuses. No adverse effects were noted in delivered offspring at 7 and 9 weeks. Female rats were given diets containing 0, 1000, 10,000 or 100,000 mg tylosin base/kg, dosed on gestation days 0-20 and killed on gestation day 20. At 100,000 mg/kg diet, body weight was depressed in dams and fetuses, and ossification was retarded. Some females from the control and the two highest dose groups were treated from gestation day 0 to postnatal day 21 and allowed to deliver. The body weight gain of offspring was lower at 100,000 mg/kg diet. Tylosin tested positive in an in vitro assay for the induction of gene mutations in mouse lymphoma cells but tested negative in an in vitro assay for the induction of gene mutations in HGPRT+ Chinese hamster ovary cells, an in vitro chromosomal damage assay in Chinese hamster ovary cells and an in vivo assay for cytogenetic damage in mouse bone marrow. ECOTOXICITY STUDIES: Tylosin was toxic in the freshwater green alga investigated over 72-hr exposures.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 解毒与急救
/SRP:/ 立即急救:确保已经进行了充分的中和。如果患者停止呼吸,请开始人工呼吸,最好使用需求阀复苏器、球囊阀面罩设备或口袋面罩,按训练操作。如有必要,执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果患者呕吐,让患者向前倾或将其置于左侧(如果可能的话,头部向下)以保持呼吸道畅通,防止吸入。保持患者安静,维持正常体温。寻求医疗救助。 /毒物A和B/
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 解毒与急救
/SRP:/ 基本治疗:建立专利气道(如有需要,使用口咽或鼻咽气道)。如有必要,进行吸痰。观察呼吸不足的迹象,如有需要,辅助通气。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……。预防癫痫发作,如有必要,进行治疗……。对于眼睛污染,立即用水冲洗眼睛。在转运过程中,用0.9%的生理盐水(NS)持续冲洗每只眼睛……。不要使用催吐剂。对于摄入,如果患者能够吞咽、有强烈的呕吐反射且不流口水,则用温水冲洗口腔,并给予5毫升/千克,最多200毫升的水进行稀释……。在去污染后,用干燥的无菌敷料覆盖皮肤烧伤……。/毒物A和B/
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). 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 0.9% saline (NS) 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 ... . /Poisons A and B/
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
硫酸泰乐菌素和磷酸泰乐菌素的药代动力学和口服生物利用度在肉鸡中进行,按照单次剂量、随机、平行设计的原则进行。两种泰乐菌素制剂以10 mg/kg体重的剂量口服和静脉给药给经过一夜禁食的鸡(每组10只鸡)。在不同时间点直至给药后24小时采集系列血样。使用高效液相色谱法测定鸡血浆中的泰乐菌素浓度。每只鸡的泰乐菌素血浆浓度-时间曲线由3P97软件进行分析。口服给药后,泰乐菌素的药代动力学最好由一室开放模型的一级吸收来描述。静脉给药后,泰乐菌素的药代动力学最好由二室开放模型来描述,硫酸泰乐菌素和磷酸泰乐菌素之间没有显著差异。口服给药后,磷酸泰乐菌素和硫酸泰乐菌素在Cmax(0.18 ± 0.01, 0.44 ± 0.09)和AUC(0.82 ± 0.05, 1.57 ± 0.25)之间存在显著差异。计算得出的硫酸泰乐菌素和磷酸泰乐菌素的口服生物利用度(F)分别为25.78%和13.73%。综上所述,我们可以合理地得出结论,口服给药后,硫酸泰乐菌素的吸收优于磷酸泰乐菌素。
The pharmacokinetics and oral bioavailability of tylosin tartrate and tylosin phosphate were carried out in broiler chickens according to a principle of single dose, random, parallel design. The two formulations of tylosin were given orally and intravenously at a dose level of 10 mg/kg b.w to chicken after an overnight fasting (n = 10 chickens/group). Serial blood samples were collected at different time points up to 24 hr postdrug administration. A high performance liquid chromatography method was used for the determination of tylosin concentrations in chicken plasma. The tylosin plasma concentration's time plot of each chicken was analyzed by the 3P97 software. The pharmacokinetics of tylosin was best described by a one-compartmental open model 1st absorption after oral administration. After intravenous administration the pharmacokinetics of tylosin was best described by a two-compartmental open model, and there were no significant differences between tylosin tartrate and tylosin phosphate. After oral administration, there were significant differences in the Cmax (0.18 + or - 0.01, 0.44 + or - 0.09) and AUC (0.82 + or - 0.05, 1.57 + or - 0.25) between tylosin phosphate and tylosin tartrate. The calculated oral bioavailability (F) of tylosin tartrate and tylosin phosphate were 25.78% and 13.73%, respectively. Above all, we can reasonably conclude that, the absorption of tylosin tartrate is better than tylosin phosphate after oral administration.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
该研究的目的是确定在健康的荷斯坦牛(n = 12)中,泰乐菌素和替米考星在血清和牛奶中的药代动力学,并重新评估牛奶中残留物的量。泰乐菌素肌内给药后,血清和牛奶中的最大浓度(C max)分别发现为1.30 ± 0.24和4.55 ± 0.23微克/毫升,达到峰值浓度所需的时间(t max)分别为2小时和4小时,消除半衰期分别为20.46 ± 2.08小时和26.36 ± 5.55小时。替米考星皮下给药后,血清和牛奶中的C max分别发现为0.86 ± 0.20和20.16 ± 1.13微克/毫升,t max分别为1小时和8小时,消除半衰期分别为29.94 ± 6.65小时和43.02 ± 5.18小时。AUCmilk/AUCserum和C max-milk/C max-serum比率,这些是用来确定药物进入牛奶速率的指标,分别为泰乐菌素的5.01 ± 0.72和3.61 ± 0.69,替米考星的23.91 ± 6.38和20.16 ± 1.13。总之,可以得出结论,泰乐菌素和替米考星在牛奶中的浓度高于预期,因此需要比报告的更长的时间才能从牛奶中清除。
/MILK/ The aim of this study is to determine the pharmacokinetics of tylosin and tilmicosin in serum and milk in healthy Holstein breed cows (n = 12) and reevaluate the amount of residue in milk. Following the intramuscular administration of tylosin, the maximum concentrations (C max) in serum and milk were found to be 1.30 + or - 0.24 and 4.55 + or - 0.23 ug/mL, the time required to reach the peak concentration (t max) was found to be 2nd and 4th hour, and elimination half-live were found to be 20.46 + or - 2.08 and 26.36 + or - 5.55 hour, respectively. Following the subcutaneous administration of tilmicosin, the C max in serum and milk were found to be 0.86 + or - 0.20 and 20.16 + or - 1.13 ug/mL, the t max was found to be 1st and 8th hr, and the elimination half life were found to be 29.94 + or - 6.65 and 43.02 + or - 5.18 hr, respectively. AUCmilk/AUCserum and C max-milk/C max-serum rates, which are indicators for determining the rate of drugs that pass into milk, were, respectively, calculated as 5.01 + or - 0.72 and 3.61 + or - 0.69 for tylosin and 23.91 + or - 6.38 and 20.16 + or - 1.13 for tilmicosin. In conclusion, it may be stated that milk concentration of tylosin after parenteral administration is higher than expected like tilmicosin and needs more withdrawal period for milk than reported.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
泰乐菌素在肉鸡体内的生物利用度和药代动力学特性在口服和静脉给药10 mg/kg剂量后被确定。通过比较口服和静脉给药的AUC值计算出的生物利用度F%,范围在30%-34%。静脉注射泰乐菌素后,药物迅速分布到机体中,表现出消除半衰期为0.52小时,分布体积(Vd)为0.69 L/kg,清除率(Cl)为5.30 +/- 0.59 mL/min/kg。口服给药后,泰乐菌素的分布体积(Vd = 0.85 L/kg)相似,而消除半衰期为2.07小时,是静脉给药后的四倍,清除率为Cl = 4.40 +/- 0.27 mL/min/kg。口服给药后泰乐菌素达到最大血药浓度的时间tmax = 1.5小时,这表明将这种抗生素与饮用水一起用于肉鸡是首选方法。然而,口服给药后泰乐菌素的最大血药浓度Cmax = 1.2微克/毫升的相对较低值表明,肉鸡使用这种抗生素的剂量应该高于其他食品生产动物。
Biological availability and pharmacokinetic properties of tylosin were determined in broiler chickens after oral and iv administration at a dose of 10 mg/kg. The calculated bioavailability--F%, by comparing AUC values--oral and AUC--iv, ranged from 30%-34%. After intravenous injection tylosin was rapidly distributed in the organism, showing elimination half-life values of 0.52 hr and distribution volume (Vd) of 0.69 L/kg, at a clearance rate (Cl) of 5.30 +/- 0.59 mL/min/kg. After oral administration, tylosin has a similar distribution volume (Vd = 0.85 L/kg), while the elimination half-life of 2.07 hr was four times bigger than after iv administration at Cl = 4.40 +/- 0.27 mL/min/kg. The obtained value tmax = 1.5 hr for tylosin after oral administration indicates that using this antibiotic with drinking water in broiler chickens is the method of choice. However, a relatively low value Cmax = 1.2 micrograms/ml after oral administration of tylosin shows that dosing of this antibiotic in broiler chickens should be higher than in other food producing animals.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
/MILK/ 牛奶中抗生素残留超过容忍水平会干扰乳制品加工,并对消费者构成潜在健康风险。残留避免计划包括遵守标签说明中指示的撤药时间等组成部分。牛奶中的抗生素在治疗后持续存在受到药物、剂量、给药途径、体重和乳腺健康状态的影响。乳腺感染(IMI)期间发生的成分变化可能会影响牛奶中抗生素的排泄,从而改变牛奶撤药时间。本研究的目的是验证一种定性微生物学方法(Charm AIM-96)检测牛复合奶中泰乐菌素的灵敏度和特异性,并确定亚临床IMI对肌内给药后泰乐菌素排泄的影响。为了测试验证,使用了两组大约120头牛;一组单次肌内注射酒石酸泰乐菌素,剂量为20 mg/kg,另一组作为未处理的对照组。测试灵敏度和特异性分别为100%和94.1%。为了确定亚临床IMI对泰乐菌素排泄的影响,两组各有七头牛,一组体细胞数(SCC)小于或等于250,000细胞/ml,另一组SCC大于或等于900,000,给予单次肌内注射酒石酸泰乐菌素,剂量为20 mg/kg。在治疗后每隔12小时采集一次牛奶样本,持续10天。低SCC和高SCC牛的牛奶泰乐菌素排泄平均分别为5天和9天(P < 0.0001)。高SCC牛的成分变化最可能影响泰乐菌素的药代动力学特性,延长抗生素在牛奶中的存在,从而影响牛奶撤药时间。
/MILK/ Antibiotic residues in milk above tolerance levels interfere with dairy product processing and pose potential health risks to consumers. Residue avoidance programmes include, among other components, the observance of withdrawal times indicated in label instructions. Persistence of antibiotics in milk following treatment is influenced by drug, dosage, route of administration, body weight and mammary gland health status. Compositional changes that take place during intramammary infection (IMI) can affect antibiotic excretion in milk, thus modifying milk withdrawal time. The objectives of this study were to validate sensitivity and specificity of a qualitative microbiological method (Charm AIM-96) to detect tylosin in bovine composite milk and to determine the influence of subclinical IMI in tylosin excretion following intramuscular administration. For test validation, two groups of approximately 120 cows were used; one received a single intramuscular injection of tylosin tartrate at a dose of 20 mg/kg, while the other group remained as untreated control. Test sensitivity and specificity were 100% and 94.1% respectively. To determine the influence of subclinical IMI in tylosin excretion, two groups of seven cows, one with somatic cell counts (SCC) < or =250 000 cells/ml and the other with SCC > or =900 000, were administered a single intramuscular injection of tylosin tartrate at a dose of 20 mg/kg. Milk samples were obtained every 12 h for 10 days following treatment. Milk tylosin excretion averaged between 5 and 9 days for cows with low and high SCC respectively (P < 0.0001). Compositional changes in cows with high SCC most likely affect the pharmacokinetic characteristics of tylosin, extending the presence of the antibiotic in milk, thus influencing milk withdrawal times.
来源:Hazardous Substances Data Bank (HSDB)

安全信息

  • 危险品标志:
    Xn
  • 安全说明:
    S36
  • 危险类别码:
    R42/43
  • 海关编码:
    2941906000
  • 危险品运输编号:
    UN 3077 9 / PGIII

SDS

SDS:c47482b9f3c002ab33d3d16675d7be8b
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制备方法与用途

抗生素——泰乐菌素

泰乐菌素是我国目前常用的一种兽用大环内酯类抗生素,亦称泰农、泰乐霉素。这种药物主要由放线菌属弗氏链霉菌经发酵提取而得,有泰乐菌素碱、磷酸盐和酒石酸盐3种形态。抗菌谱与红霉素相似,对革兰阳性菌和一些革兰阴性菌、霉形体、弧菌、球虫、螺旋体等均有抑制作用,尤其是对霉形体特别有效,但其对革兰阳性菌的作用不如红霉素。

泰乐菌素的一个重要特点是它对抗支原体作用强大,是大环内酯类中抗支原体作用最强的药物之一。作为饲料添加剂,广泛用于鸡、猪、牛、羊及鱼、虾等动物的饲料中,可促进畜禽生长、提高饲料利用率。主要用于防治鸡、火鸡和其他动物的支原体病;猪的弧菌性痢疾、传染性胸膜肺炎,以及敏感菌所引起的肠炎、肺炎、乳腺炎、子宫内膜炎等。

泰乐菌素治疗鸡慢性呼吸道病的效果良好,皮下注射效果优于内服。皮下注射后,组织中药物浓度比内服高2~3倍,有效血药浓度维持时间亦较长。磷酸泰乐菌素还用作牛、猪、鸡的促生长药物饲料添加剂。

泰乐菌素与红霉素存在交叉耐药性。

1962年,美国礼来公司成功开发出泰乐菌素并推向市场,主要用于饲料添加剂和动物治疗。其能明显促进畜禽生长提高饲料利用率,在体内主要以泰乐碱的形式存在。泰乐菌素可在原核生物的核糖体中与23S rRNA结合,从而阻碍氨基酸掺入肽链合成,抑制感染菌蛋白质的合成。该药物具有较强的组织穿透力、口服吸收快和广泛分布于肺、肝、肾、脾和胆囊等器官中的特点,生物利用率高,起效迅速,并能保持有效抑菌浓度较长时间。

泰乐菌素在停药后排泄快、残留量少且安全性较高。其本身性质稳定,在饲料的常规调制过程中对其有效成分的影响极小。连续低剂量服用不仅能预防疾病,还能显著促进动物生长,缩短饲养周期。此外,泰乐菌素是畜禽专用抗生素,避免了人畜共用抗生素易发生的交叉耐药性问题。

生物活性

Tylosin 是一种兽医用大环内酯类抗生素,是 Streptomyces fradiae 的产物。它对革兰氏阳性菌具有高效的抗菌活性,并广泛用于促进动物生长的饲料添加剂,可用于治疗家禽、猪和牛的细菌性痢疾和呼吸道疾病。

靶点

泰乐菌素通过与细菌核糖体 50S 核糖体亚单位中的 23S rRNA 结合而发挥抗茵作用。体内研究显示,泰乐菌素(10-500 mg/kg;皮下注射)可抑制由脂多糖 (LPS) 引起的 TNF-α 和 IL-1β 水平升高,并增加 IL-10 的水平。在 Balb/C 小鼠模型中,分别给予 10 mg/kg、100 mg/kg 和 500 mg/kg 剂量后,LPS (250 µg) 处理的小鼠的 TNF-α 和 IL-1β 水平降低而 IL-10 水平增加。

用途

泰乐菌素主要用于抗菌治疗。