[(1S,2R,3S,4S,6R,7R,8S,14R)-4-ethenyl-3-hydroxy-2,4,7,14-tetramethyl-9-oxo-6-tricyclo[5.4.3.01,8]tetradecanyl] 2-[2-(diethylamino)ethylsulfanyl]acetate

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: [(1S,2R,3S,4S,6R,7R,8S,14R)-4-ethenyl-3-hydroxy-2,4,7,14-tetramethyl-9-oxo-6-tricyclo[5.4.3.01,8]tetradecanyl] 2-[2-(diethylamino)ethylsulfanyl]acetate
• 化学式: C₂₈H₄₇NO₄S
• 分子量: 493.7
• InChiKey: UURAUHCOJAIIRQ-LNPVQEOXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  34
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  92.1
• 氢给体数：
  1
• 氢受体数：
  6

ADMET

代谢

在蛋鸡、肉鸡和火鸡（每组6只动物）口服剂量为10毫克/千克体重/天的（3）H-替米硝唑氢富马酸，连续5天，组织提取物中检测到超过15种代谢物，但大部分残留物由4种代谢物组成。在家禽组织中，没有单个代谢物代表超过30%的总残留物。

In laying hens, broilers and turkeys (6 animals per group) orally dosed with 10 mg (3)H-tiamulin hydrogen fumarate/kg bw/day for 5 consecutive days, over 15 metabolites were detected in tissue extracts but most of the residue was accounted for by 4 metabolites. No individual metabolite represented more than 30% of the total residue in poultry tissues.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在口服土霉素处理的猪肝中，能够水解成8-α-羟基甲基丁醇（即标志残留物）的代谢物百分比分别为：处理后4小时3.5%，24小时3.6%，96小时5.7%。

In the liver of pigs orally treated with tiamulin, the percentage of the metabolites that can be hydrolyzed to 8-alpha-hydroxymutilin (ie marker residue) to total residues was 3.5, 3.6 and 5.7% at 4, 24 and 96 hours after treatment, respectively.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在给予自由采食含替米考星39毫克/公斤饲料的猪（每性别每组4只动物）连续10天的情况下，通过气相色谱与电化学检测法检测到的，可以在肝脏中水解形成8-α-羟基 mutilin 的代谢物平均浓度为：在给药后2小时和12小时分别为447和247微克当量/公斤。在连续18天给药的动物中，给药后12、16、20和24小时，肝脏中8-α-羟基 mutilin 的平均浓度分别为184、256、214和175微克当量/公斤。

In pigs (4 animals per sex and group) given ad libitum access to feed containing tiamulin at a concentration of 39 mg/kg for 10 consecutive days, the average concentrations of metabolites in liver that could be hydrolyzed to form 8-alpha-hydroxymutilin, as detected by gas chromatography with electrochemical detection, were 447 and 247 ug equivalent/kg at 2 and 12 hours after dosing, respectively. In animals does for 18 consecutive days, the average concentrations of 8-alpha-hydroxymutilin in liver were 184, 256, 214 and 175 ug equivalents/kg at 12, 16, 20 and 24 hours after dosing, respectively.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在口服(3)H-泰妙菌素的猪体内，胆汁和尿液样本中的总残留物中，6-去甲基泰妙菌素的比例不到1%，并且当通过琼脂平板扩散法进行测试时，其抗菌活性为泰妙菌素的67%。另外四种代谢物相对于泰妙菌素的抗菌活性在0.7%到3.3%之间，所有其他代谢物的相对活性都小于0.3%。

In pigs orally dosed with (3)H-tiamulin, 6-desmethyltiamulin accounted for less than 1% of the total residue in bile and urine samples and had 67% of the antimicrobiological activity of tiamulin when tested by agar plate diffusion. Four other metabolites were found to have antimicrobiological activities relative to tiamulin of between 0.7 and 3.3% and all other metabolites had relative activities of less than 0.3%.

来源:Hazardous Substances Data Bank (HSDB)

代谢

泰乐菌素被广泛代谢成超过20种代谢物，其中一些具有抗菌活性。大约30%的这些代谢物通过尿液排出，其余的通过粪便排出。

Tiamulin is extensively metabolized to over 20 metabolites, some having antibacterial activity. Approximately 30% of these metabolites are excreted in the urine with the remainder excreted in the feces.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

本研究调查了大鼠中莫能菌素和泰妙菌素之间毒性相互作用的特性。在第一阶段，进行了一项为期三天的比较口服重复剂量毒性研究，研究了莫能菌素和泰妙菌素各自的效应（分别为莫能菌素10、30和50毫克/千克或泰妙菌素40、120和200毫克/千克体重）。在第二阶段，同时给予这两种化合物以研究毒性相互作用（分别为莫能菌素10毫克/千克和泰妙菌素40毫克/千克体重）。结果显示，莫能菌素在大鼠中以30和50毫克/千克的剂量具有毒性。泰妙菌素在200毫克/千克的剂量下耐受性良好。联合给药后，出现了毒性迹象（包括雌性动物的致死性）。莫能菌素在给予50毫克/千克的动物中引起了剂量依赖性的心脏毒性效应和骨骼肌的空泡变性。两种化合物在高剂量下都对肝脏产生了毒性效应。同时给药后，肝脏出现了轻微的效应（仅限雌性），心肌的水肿变性和骨骼肌的空泡变性。在骨骼肌中观察到的改变比单独给予50毫克/千克莫能菌素时更为明显。

The characteristics of the toxic interaction between monensin & tiamulin were investigated in rats. A three-day comparative oral repeated-dose toxicity study was performed in Phase I, when the effects of monensin & tiamulin were studied separately (monensin 10, 30, & 50 mg/kg or tiamulin 40, 120, & 200 mg/kg body weight, respectively). In Phase II, the two compounds were administered simultaneously to study the toxic interaction (monensin 10 mg/kg & tiamulin 40 mg/kg b.w., respectively). Monensin proved to be toxic to rats at doses of 30 & 50 mg/kg. Tiamulin was well tolerated up to the dose of 200 mg/kg. After combined admin, signs of toxicity were seen (including lethality in females). Monensin caused a dose-dependent cardiotoxic effect & vacuolar degeneration of the skeletal muscles in the animals given 50 mg/kg. Both compounds exerted a toxic effect on the liver in high doses. After simultaneous admin of the two compounds, there was a mild effect on the liver (females only), hydropic degeneration of the myocardium & vacuolar degeneration of the skeletal muscles. The alteration seen in the skeletal muscles was more marked than that seen after the admin of 50 mg/kg monensin alone.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

进行了研究，以调查莫能菌素和泰妙菌素以及同时给予这两种化合物对大鼠微粒体酶的影响。在实验的第一阶段，分别研究了莫能菌素和泰妙菌素的影响（莫能菌素分别为10、30和50毫克/千克，泰妙菌素分别为40、120和200毫克/千克体重），而在第二阶段，两种化合物同时给药（莫能菌素10毫克/千克和泰妙菌素40毫克/千克体重）。当单独给予莫能菌素时，它对微粒体肝酶没有显著影响。在某些情况下，观察到某些酶活性的轻微抑制。泰妙菌素引起了剂量依赖性的肝酶诱导。低剂量（分别为10和40毫克/千克）的莫能菌素和泰妙菌素联合给药导致P450相关酶活性显著升高。酶诱导在雌性中比在雄性中更为明显。结果表明，泰妙菌素的同時给药可能会影响莫能菌素的生物转化，可能增加了这种离子载体抗生素的反应代谢物（们）的量。

Studies were carried out to investigate the effects of monensin & tiamulin, & the simultaneous admin of both compounds on microsomal enzymes in rats. In Phase I of the experiments the effects of monensin & tiamulin were studied separately (monensin 10, 30, & 50 mg/kg or tiamulin 40, 120, & 200 mg/kg body weight, respectively), while in Phase II the two compounds were administered simultaneously (monesin 10 mg/kg & tiamulin 40 mg/kg b.w., respectively). When monensin was administered by itself, it exerted no significant effect on microsomal liver enzymes. In a few cases, slight inhibition of certain enzyme activities was seen. Tiamulin provoked a dose-dependent hepatic enzyme induction. The combined admin of monensin & tiamulin at low doses (10 & 40 mg/kg, respectively) resulted in marked elevation of P450-related enzyme activities. The enzyme induction was more pronounced in females than in males. The results suggest that the simultaneous admin of tiamulin may influence the biotransformation of monensin, possibly increasing the amount of reactive metabolite(s) of the ionophore antibiotic.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

泰乐菌素是一种在兽医医学中经常使用的抗生素。该药物已被证实与其他同时给药的化合物产生临床重要的相互作用。采用稳定表达人细胞色素P450（EC 1.14.14.1）cDNA（CYP3A4）的NIH/3T3细胞系来研究泰乐菌素对CYP3A4活性的影响。与载体转染细胞相比，在CYP3A4表达细胞中增加的睾酮6β-羟基化活性在用1微米泰乐菌素孵育后显示出降低的活性，在用2、5和10微米泰乐菌素孵育后完全降低到背景水平。将CYP3A4表达细胞系与含有细菌lacZ'基因的穿梭载体结合使用，研究泰乐菌素对CYP3A4介导的黄曲霉毒素B1突变性的影响。泰乐菌素可以完全抑制CYP3A4表达细胞中黄曲霉毒素B1的突变频率，但对直接诱变剂甲基磺酸乙酯的突变频率没有影响。对CYP3A4表达细胞系的匀浆进行西方印迹分析，结果显示泰乐菌素孵育后CYP3A4蛋白稳定性增加，支持泰乐菌素的抑制作用机制是通过与细胞色素结合的假设。

Tiamulin is an antibiotic frequently used in veterinary medicine. The drug has been shown to produce clinically important interactions with other compounds that are administered simultaneously. An NIH/3T3 cell line, stably expressing human cytochrome P450 (EC 1.14.14.1) cDNA (CYP3A4), was used to study the effect of tiamulin on CYP3A4 activity. The 6 beta-hydroxylation activity of testosterone, which is increased in CYP3A4-expressing cells compared to vector-transfected cells, showed reduced activity after incubation with 1 microM tiamulin and was completely reduced to background level after incubation with 2, 5 and 10 microM tiamulin. The CYP3A4-expressing cell line was used in combination with a shuttle vector containing the bacterial lacZ' gene to study the effect of tiamulin on CYP3A4-mediated mutagenicity of aflatoxin B1. The mutation frequency of aflatoxin B1 could be completely inhibited by tiamulin in CYP3A4-expressing cells, but no effect was observed on the mutation frequency of the direct mutagen ethylmethanesulphonate. Western blotting of homogenates of the CYP3A4-expressing cell line showed stabilization of CYP3A4 protein after incubation with tiamulin, supporting the hypothesis that the mechanism of inhibition is by binding of tiamulin to the cytochrome.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在家禽中，泰妙菌素会干扰莫能菌素和盐霉素的代谢，如果这些药物同时使用，它们会变得有毒。

In poultry, tiamulin interferes with monensin and salinomycin metabolism, and if the drugs are fed together, they become toxic.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：泰妙菌素，当连续五天通过饮水给药时，是一种有效的抗生素，用于治疗与布氏螺旋体（以前称为螺旋体或梅毒螺旋体）相关的猪痢疾，以及治疗由胸膜肺炎放线杆菌引起的猪肺炎。作为饲料添加剂，它被用来增加猪的体重。人类暴露和毒性：0.05%泰妙菌素制剂的局部给药没有引起皮肤刺激或敏感。另一项研究在6名健康的男性志愿者中进行。三名志愿者分别口服5剂，剂量从0.125增加到7.2 mg/kg体重，每剂之间间隔72小时。其余志愿者口服单剂，剂量范围为8.2至10.7 mg/kg体重泰妙菌素。血压、血清化学或心电图没有出现与物质相关变化。动物研究：泰妙菌素的过量使用在猪身上产生了短暂的流涎、呕吐和明显的镇静作用。在一项亚慢性研究中，大鼠被喂食含有0.5或30 mg泰妙菌素/kg体重/天的食物，持续26周。进一步的大鼠组接受了180 mg/kg体重/天，持续10周，然后是270 mg/kg体重/天，持续16周；一组在治疗结束时进行尸检，其余大鼠在未经处理的对照饮食中再维持4或8周。在180 mg/kg体重组中，血清胆固醇和饮水摄入量增加。当剂量增加到270 mg/kg体重/天时，效果包括血清碱性磷酸酶、丙氨酸磷酸酶、丙氨酸转氨酶和天冬氨酸转氨酶的增加。还观察到腹部膨胀、大便密集和尿比重增加。雌雄两性的绝对和相对肝重量增加，在组织病理学检查中观察到肝脏脂肪浸润。在一项慢性研究中，狗每天口服0、3、10或30 mg/kg体重/天的泰妙菌素，持续54周。在给予10和30 mg/kg体重/天的组中，偶尔观察到呕吐，血清钾浓度降低，心电图显示QT间期延长。血清乳酸脱氢酶（LDH）显著增加；与心脏相关的同工酶LDH1没有增加。大鼠被喂食含有泰妙菌素的食物，浓度设计为提供0、2、8或32 mg/kg体重/天的摄入量，持续30个月。任何肿瘤类型的发病率没有显著的剂量相关趋势。在另一项研究中，小鼠被喂食含有相当于0、1、6或48 mg/kg体重/天的泰妙菌素的食物，持续最多123周。任何肿瘤类型的发病率没有显著的剂量相关趋势。怀孕的雌性大鼠从怀孕的第6天到第15天每天口服0、30、100或300 mg/kg体重/天的剂量。在300 mg/kg体重/天时，出现了轻微的母体毒性迹象。在这个剂量水平上，平均胎儿体重降低，骨骼发育迟缓的发病率增加。没有发现致畸性。怀孕的雌性家兔从怀孕的第6天到第18天每天口服0、30、55或100 mg/kg体重/天的剂量。55 mg/kg体重/天及以上的剂量导致了一些母体的死亡，母体体重增加减少。在55 mg/kg体重/天及以上的剂量下，产仔数和胎儿体重减少。在任何剂量水平下都没有发现致畸性。在猪上进行了几项生殖研究。繁殖母猪在怀孕的第84天到第92天喂食含有200 mg/kg饲料的食物，另一组在配种后2天开始维持含有16 mg/kg体重/天的食物，持续6周，进一步的组在怀孕期间的不同时期以及在某些情况下直到仔猪断奶期间通过饮水给予8.8 mg/kg体重/天的泰妙菌素。对母猪的健康、怀孕、分娩、产仔数、仔猪的生长和存活、发情周期或后续繁殖性能没有不利影响。当繁殖公猪在14天内喂食含有16 mg/kg体重/天的食物时，对健康状态、性欲或精液质量没有影响。泰妙菌素没有诱导鼠伤寒沙门氏菌TA98、TA100、TA1535、TA1537或TA1538菌株的基因突变。在V79中国仓鼠细胞HPRT位点的体外基因突变分析也给出了阴性结果。在小鼠体内微核试验中，泰妙菌素对微核多染红细胞的发生频率没有影响。

IDENTIFICATION AND USE: Tiamulin, when administered in the drinking water for five consecutive days, is an effective antibiotic for the treatment of swine dysentery associated with Brachyspira (formerly Serpulina or Treponema) and for treatment of swine pneumonia due to Actinobacillus pleuropneumoniae. As a feed additive, it is used to cause increased weight gain in swine. HUMAN EXPOSURE AND TOXICITY: Topical administration of a 0.05% formulation of tiamulin did not cause skin irritation or sensitization. Another study was carried out in 6 healthy male human volunteers. Three volunteers were given 5 oral doses progressing from 0.125 to 7.2 mg/kg bw with 72 hours between each dose. The remaining volunteers were given a single oral dose in the range of 8.2 to 10.7 mg/kg bw tiamulin. There was no substance-related changes in blood pressure, serum chemistry or electrocardiograms. ANIMAL STUDIES: Overdoses of tiamulin have produced transitory salivation, vomiting and an apparent calming effect on the pig. In a subchronic study, rats were fed diets containing 0.5 or 30 mg tiamulin/kg bw/day for 26 weeks. Further groups of rats received 180 mg/kg bw/day for 10 weeks, followed by 270 mg/kg bw/day for 16 weeks; one group was necropsied at the end of treatment, the remaining rats were maintained on untreated control diets for a further 4 or 8 weeks. There were increases in serum cholesterol and in water intake in the 180 mg/kg bw group. When the dose was increased to 270 mg/kg bw/day, the effects included increased serum alkaline phosphatase, alanine phosphatase, alanine aminotransferase and aspartate aminotransferase. Abdominal distension, dense feces and increased urine specific gravity were also observed. Absolute and relative liver weights were increased in both sexes and fatty infiltration of the liver was observed on histopathological examination. In a chronic study, dogs were given daily oral doses of 0, 3, 10 or 30 mg/kg bw/day of tiamulin for 54 weeks. In the groups given 10 and 30 mg/kg bw/day, occasional emesis was observed, serum potassium concentrations were decreased and electrocardiograms showed prolongation of the QT interval. Serum lactate dehydrogenase (LDH) was significantly increased; there was no increase in the cardiac-related isoenzyme LDH1. Rats were fed diets containing tiamulin at concentrations designed to provide intakes of 0, 2, 8 or 32 mg/kg bw/day of tiamulin for 30 months. There was no significant dose-related trend in the incidence of any tumor type. In another study, mice were fed diets containing the equivalent of 0, 1, 6 or 48 mg/kg bw/day of tiamulin for up to 123 weeks. There was no significant dose-related trend in the incidence of any tumor type. Pregnant female rats were given daily oral doses of 0, 30, 100 or 300 mg/kg bw/day from days 6 to 15 of gestation. At 300 mg/kg bw/day there were minor signs of maternal toxicity. At this dose level, the mean fetal weight was reduced and there was an increased incidence of retarded skeletal development. There was no evidence of teratogenicity. Pregnant female rabbits were given daily oral doses of 0, 30, 55 or 100 mg/kg bw/day from days 6 to 18 of gestation. Doses of 55 mg/kg bw/day and above caused the deaths of some dams and maternal body weight gain was reduced. Litter size and fetal weights were reduced at 55 mg/kg bw/day and above. There was no evidence of teratogenicity at any dose level. Several reproductive studies were performed in pigs. Breeding sows were fed a diet containing 200 mg/kg feed from days 84 to 92 of gestation, another group was maintained on a diet containing 16 mg/kg bw/day from 2 days after mating for 6 weeks, and further groups were given tiamulin in the drinking water at a dose of 8.8 mg/kg bw/day for various periods during gestation and in some cases up to weaning of the offspring. There were no adverse effects on health of the sows, pregnancy, parturition, letter size, growth and survival of the piglets, estrus cycle or subsequent breeding performance. When given to breeding boars, at a diet containing 16 mg/kg bw/day for 14 days, there were no effects on health status, libido or semen quality. Tiamulin did not induce gene mutations in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 or TA1538. An in vitro assay for gene mutation at the HPRT locus of V79 Chinese hamster cells also gave negative results. In an in vivo micronucleus test in mice tiamulin had no effect on the frequency of micronucleated polychromatic erythrocytes.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

它很容易从肠道吸收，在服药后30分钟内就可以在血液中找到。

It is readily absorbed from the gut and can be found in the blood within 30 minutes after dosing.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

癸甲溴铵通过口服方式被猪很好地吸收。大约85%的剂量被吸收，单次口服剂量后2到4小时达到峰值水平。癸甲溴铵似乎分布良好，肺中浓度最高。

Tiamulin is well absorbed orally by swine. Approximately 85% of a dose is absorbed and peak levels occur between 2-4 hours after a single oral dose. Tiamulin is apparently well distributed, with highest levels found in the lungs.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在猪（每个性别和组2只动物）中，口服给药5毫克（14）C-替米考星碱/千克体重/天，连续10天，约35%的剂量通过尿液排出，65%通过粪便排出。停药10天后，肝脏、肾脏、肌肉和脂肪中的总残留浓度分别为21,880、600、720和720微克当量/千克，停药25天后分别为480、220、430、910微克当量/千克。

In pigs (2 animals per sex and group), following oral administration of 5 mg (14)C-tiamulin base/kg bw/day for 10 consecutive days, approximately 35% of the dose was eliminated in urine and 65% in feces. The total residue concentrations in liver, kidney, muscle and fat were 21,880, 600, 720 and 720 ug equivalents/kg, respectively, 10 days after dosing and 480, 220, 430, 910 ug equivalents/kg after 25 days.

来源:Hazardous Substances Data Bank (HSDB)