Epi-doramectin | 117704-25-3

• 物质功能分类: 原料药 - 抗寄生虫病药 - 抗蠕虫药
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯类和类似物
• 英文名称: Epi-doramectin
• 英文别名: 2-cyclohexyl-21',24'-dihydroxy-12'-[5-(5-hydroxy-4-methoxy-6-methyloxan-2-yl)oxy-4-methoxy-6-methyloxan-2-yl]oxy-3,11',13',22'-tetramethylspiro[2,3-dihydropyran-6,6'-3,7,19-trioxatetracyclo[15.6.1.14,8.020,24]pentacosa-10,14,16,22-tetraene]-2'-one
• CAS: 117704-25-3
• 化学式: C₅₀H₇₄O₁₄
• 分子量: 899.1
• InChiKey: QLFZZSKTJWDQOS-UHFFFAOYSA-N

物化性质

• 熔点：
  116-1190C
• 沸点：
  967.4±65.0 °C(Predicted)
• 密度：
  1.25±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于甲醇：
• LogP：
  4.39-4.43 at 25℃

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  64
• 可旋转键数：
  7
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  170
• 氢给体数：
  3
• 氢受体数：
  14

ADMET

代谢

以三氚标记的5位多拉菌素单次给药于Sprague-Dawley大鼠（2只雄性，通过灌胃给予5 mg/kg体重的丙二醇：甘油），一只比格犬（1只雌性，通过灌胃给予3.5 mg/kg体重的芝麻油）和牛（5只雄性，皮下给予0.2 mg/kg体重）。从每个物种的肝脏和粪便以及牛的脂肪中鉴定出以下代谢物...未改变的多拉菌素，3"-O-去甲基多拉菌素，24-羟甲基多拉菌素和24-羟甲基-3"-O-去甲基多拉菌素。

Doramectin labelled with tritium in the 5-position was administered as a single dose to Sprague-Dawley rats (2 males given 5 mg/kg bw in propylene glycol:glycerol by gavage), a beagle dog (1 female given 3.5 mg/kg bw in sesame oil by gavage) and cattle (5 males given 0.2 mg/kg bw subcutaneously). /The following metabolites were identified in/... the liver and feces from each species and the fat of cattle... /unchanged doramectin, 3"-O-desmethyl doramectin, 24-hydroxymethyl doramectin, and 24-hydroxymethyl-3"-O-desmethyl doramectin./

来源:Hazardous Substances Data Bank (HSDB)

代谢

多拉霉素的代谢产物在所有研究的物种（大鼠、狗、猪、牛）中相似。这些代谢物比多拉霉素更具极性，是由于远端糖环的脱甲基化、24-甲基羟基化以及这两种生物转化的结合产物。

The products of doramectin metabolism were similar in all species investigated /rats, dogs, pigs, cattle/. The metabolites were more polar than doramectin and were the result of O-demethylation in the distal saccharide ring, of hydroxylation of the 24-methyl group and a combination of both of these biotransformations.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。必要时进行吸痰。观察呼吸不足的迹象，并在需要时辅助通气。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，并在必要时进行治疗……。监测休克，并在必要时进行治疗……。预期可能出现癫痫，并在必要时进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）连续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能够吞咽、有强烈的咳嗽反射且不流口水，则用水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒物A和B/

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)

毒理性

• 解毒与急救

高级治疗：对于昏迷、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿...。对于严重的支气管痉挛，可以考虑使用β激动剂，如沙丁胺醇...。监测心率和必要时治疗心律失常...。开始静脉输注D5W/SRP：“保持开放”，最低流速/。如果出现低血容量的迹象，使用0.9%的生理盐水（NS）或乳酸钠林格液。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象...。用地西泮或劳拉西泮治疗癫痫...。使用丙美卡因氢氯化物协助眼部冲洗...。/毒物A和B/

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验室动物：急性暴露/多拉菌素以0.5克量在闭合贴片下应用于3只新西兰白兔的正常和磨损皮肤上，持续24小时。在剂量后24小时和48小时，1个完整部位和2个磨损部位观察到轻微红斑。在任何部位都没有水肿，且在剂量后72小时所有部位看起来都正常。

/LABORATORY ANIMALS: Acute Exposure/ Doramectin was applied to normal and abraded skin of 3 New Zealand white rabbits (0.5 g under an occlusive patch) for 24 hours. Slight erythema was observed 24 and 48 hours post-dose at 1 of 3 intact sites and 2 of 3 abraded sites. There was no edema at any site and all sites appeared normal 72 hours post-dose.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验室动物：亚慢性或前慢性暴露/ CD-1小鼠组（每组10只/性别/剂量）在饮食中给予多拉菌素（纯度94.1%）43天。目标剂量为0、10、20、40或60 mg/kg bw/天，在第1至14天；0、10、20、80或100 mg/kg bw/天，在第15至28天；以及0、100、200、400或600 mg/kg bw/天，在第29至43天。毒性迹象包括400和600 mg/kg bw/天时的倦怠、弓背姿势和震颤，以及100和200 mg/kg bw/天时一些小鼠的弓背和未梳理外观。一些给予400和600 mg/kg bw/天的动物在濒死时被牺牲，这些组别中的剩余小鼠在第33天被杀死。体重或食物消耗没有受到影响。大多数处理组的相对肝重量略高，但变化不大且与剂量无关。临床实验室参数和病理学检查未进行。

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Groups of CD-1 mice (10/sex/dose) were administered doramectin (purity 94.1%) in the diet for 43 days. Target doses were 0, 10, 20, 40, or 60 mg/kg bw/day on days 1 to 14; 0, 10, 20, 80 or 100 mg/kg bw/day on days 15 to 28; and 0, 100, 200, 400 or 600 mg/kg bw/day on days 29 to 43. Toxic signs included lethargy, hunched posture and tremors at 400 and 600 mg/kg bw/day, and hunched and ungroomed appearance in some mice at 100 and 200 mg/kg bw/day. A number of animals given 400 and 600 mg/kg bw/day were sacrificed moribund and the remaining mice in these groups were killed on day 33. There were no effects on body weight or food consumption. Relative liver weights were slightly higher in most treated groups but the changes were minor and not dose-related. Clinical laboratory parameters and pathological examinations were not carried out.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验室动物：亚慢性或预慢性暴露/ CD-1小鼠组（每组10只/性别）在92天内通过饲料摄入多拉菌素（纯度94.1%）。目标剂量为0、100、200或300 mg/kg体重/天。实际多拉菌素摄入量为83-121、154-191或221-322 mg/kg体重/天。在中剂量和高剂量组观察到震颤、蜷缩姿势、不整洁外观和嗜睡，导致300 mg/kg体重/天的9只小鼠和200 mg/kg体重/天的3只小鼠死亡或濒死牺牲。这两个组中剩余的动物分别在第12天或第19天被处死。在200 mg/kg体重/天及以上，体重增加与食物消耗减少有关。血清肌酐和BUN在100 mg/kg体重/天略有增加，在高剂量下没有影响，可能是由于这些组小鼠早期被淘汰。血液学参数未受影响。所有处理组肝脏重量增加，出现中心小叶肝细胞肥大，仅在100 mg/kg体重/天出现多核非增殖肝细胞。死亡和濒死动物显示淋巴器官淋巴细胞溶解，骨髓细胞减少和肾上腺皮质坏死，这可能是由于压力和体重减轻。

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Groups of CD-1 mice (10/sex/group) were fed doramectin (purity 94.1%) in the diet for 92 days. Target doses were 0, 100, 200 or 300 mg/kg bw/day. Actual doramectin intake was 83-121, 154-191 or 221-322 mg/kg bw/day. Tremors, hunched posture, unkempt appearance and lethargy were observed at the mid- and high-dose groups and resulted in death or moribund sacrifice of 9 mice at 300 mg/kg bw/day and 3 mice at 200 mg/kg bw/day. The remaining animals in these two groups were killed on day 12 or 19, respectively. Body-weight gain was depressed in association with reduced food consumption at 200 mg/kg bw/day and above. Serum creatinine and BUN were slightly increased at 100 mg/kg bw/day with no effects at higher doses, presumably due to early culling of mice in these groups. Hematological parameters were unaffected. All treated groups had increased liver weights and hypertrophy of centrilobular hepatocytes, with multinucleate non-proliferative liver cells at 100 mg/kg bw/day only. Dead and moribund animals showed lymphocyte lysis in lymphoid organs, cellular depletion of bone marrow and necrosis of the adrenal cortex which may have resulted from stress and weight loss.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在第一项研究中，10头乳用荷斯坦牛被用0.58毫克/千克体重的多拉菌素外用制剂治疗，并在56天后用相同剂量再次治疗。... 在第一次和第二次治疗后的49天和10天分别收集了牛奶样本。在治疗后的头7天，每天收集两次样本，在第10、13、16、19、22、25、28、32、36、40和49天每天收集一次。在再次治疗时，治疗后的头7天每天收集两次样本，在第10天收集一次。... 治疗后72小时，牛奶中多拉菌素残留物的浓度增加到最大平均值为22毫克/千克。多拉菌素残留物的平均浓度在384小时（16天）时降至低于定量限（3毫克/千克）。再次治疗后，多拉菌素残留物的浓度逐渐增加到在给药后48小时达到最大平均值为12毫克/千克；在给药后240小时（10天）降至<4毫克/千克。在给药后的第1、4和10天进行了牛奶/脂肪分析。在这些时间点牛奶脂肪中多拉菌素残留物的平均浓度分别为171毫克/千克、501毫克/千克和114毫克/千克。牛奶脂肪中多拉菌素残留物的浓度因子分别为29.6、32.2和24.7。

In the first study, 10 dairy Holstein cows were treated with a pour-on formulation of doramectin at a dose of 0.58 mg/kg bw and were retreated with the same dose 56 days later. ... Samples of milk were collected for 49 days and 10 days, respectively, after the first and second treatments. Samples were collected twice daily until day 7, and once daily on days 10, 13, 16, 19, 22, 25, 28, 32, 36, 40 and 49. On retreatment, samples were taken twice daily until day 7 and once at day 10. ... The concentrations of doramectin residue in milk increased to a maximum mean value of 22 mg/kg at 72 hr after treatment. Mean concentrations of doramectin residues decreased to below the limit of quantitation (3 mg/kg) at 384 hr (16 days). After retreatment, concentrations of doramectin residues increased gradually to a maximum mean value of 12 mg/kg at 48 hr after dosing; and decreased to <4 mg/kg at 240 hr (10 days) after dosing. The milk/fat analyses were conducted 1, 4, and 10 days after dosing. Mean concentrations of doramectin residues in the milk fat at these time points were 171 mg/kg, 501 mg/kg and 114 mg/kg, respectively. Concentration factors for doramectin residues in milk fat were 29.6, 32.2 and 24.7, respectively.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在第二项研究中，10头牛通过局部涂抹0.58毫克/公斤剂量的多拉菌素（doramectin）进行了一次治疗，并在56天后以同样的剂量进行了再次治疗。每天两次收集牛奶样本。牛奶中多拉菌素的浓度在治疗后45小时达到最大平均值9毫克/公斤，并在治疗后237小时（10天）降至低于定量限（LOQ）。在第56天再次治疗后，残留物的浓度在93小时后增加到平均最大值8毫克/公斤，并在237小时（10天）后降至低于LOQ。牛奶脂肪中多拉菌素残留物的平均浓度在第1、4和10天分别为91�