Pharmakon1600-01505902 | 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: Pharmakon1600-01505902
• 英文别名: (1'R,2R,3S,4'S,6S,8'R,10'E,12'S,13'S,14'E,16'E,20'R,21'R,24'S)-2-cyclohexyl-21',24'-dihydroxy-12'-[(4S,6S)-5-[(2S,4S,5S,6S)-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-CYHFSSRLSA-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给SD大鼠（2只雄性，以丙二醇：丙三醇灌胃5 mg/kg体重）、一只比格犬（1只雌性，以芝麻油灌胃3.5 mg/kg体重）和牛（5只雄性，皮下给药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了以下代谢物……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（如需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。密切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……。预防癫痫发作，并在必要时进行治疗……。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）连续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的干呕反射且不流口水，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：对于昏迷的患者、严重肺水肿的患者或严重呼吸困难的患着，考虑进行口咽或鼻咽气管插管以控制气道。使用带阀口罩的袋装呼吸机进行正压通气技术可能有益。考虑对肺水肿进行药物治疗...。对于严重的支气管痉挛，考虑使用β受体激动剂，如沙丁胺醇（舒喘灵）...。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”，最低流量/。如果出现低血容量的迹象，使用0.9%的生理盐水（NS）或乳酸钠林格氏液。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...。使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...。/毒素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/多拉菌素被应用于3只新西兰白兔的正常和磨损皮肤（在封闭贴片下0.5克）24小时。在剂量后24小时和48小时，1个完整部位和3个磨损部位中的2个部位观察到轻微红斑。在任何部位都没有水肿，并且所有部位在剂量后72小时看起来正常。

/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）通过饮食给药多拉菌素（纯度94.1%）持续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。毒性迹象包括在400和600 mg/kg bw/天时的乏力、弓背姿势和震颤，以及在100和200 mg/kg bw/天时一些小鼠出现弓背和未梳理的外观。一些给予400和600 mg/kg bw/天的动物在濒死状态时被牺牲，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脏重量略高，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。这两个组的剩余动物分别在第12天或第19天被杀死。在200 mg/kg体重/天及以上，体重增加与食物摄入量减少有关。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，可能是由于这些组的小鼠早期被淘汰。血液学参数未受影响。所有处理组都有肝脏重量增加和中央静脉肝细胞肥大，仅在100 mg/kg体重/天出现多核非增殖性肝细胞。死亡和濒死动物显示出淋巴器官中的淋巴细胞溶解、骨髓细胞减少和肾上腺皮质的坏死，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毫克/公斤、142毫克/公斤和55毫克/公斤。牛奶脂肪与牛奶中多拉菌素残留物的浓度因子分别为14.2、20.9和14.1。

In the second study, 10 cows were treated with doramectin by topical application of a pour-on formulation at a dose of 0.58 mg/kg and were re-treated with the same dose 56 days later. Samples of milk were collected twice daily. Concentrations of doramectin in milk increased to a maximum mean value of 9 mg/kg at 45 hr after treatment and decreased to below the LOQ by 237 hr (10 days) after treatment. After re-treatment on day 56, concentrations of residues increased to a mean maximum value of 8 mg/kg after 93 hr and decreased to less than the LOQ after 237 hr (10 days). Mean concentrations of doramectin residues in the milk fat at 1, 4, and 10 days were 91 mg/kg, 142 mg/kg and 55 mg/kg, respectively. Concentration factors for doramectin residues in milk fat versus milk were 14.2, 20.9 and 14.1, respectively.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

第三项研究确定了在哺乳期牛皮下注射多拉菌素制剂0.23毫克/千克体重后，多拉菌素残留的消减情况，并在56天后以相同剂量再次治疗。多拉菌素在牛奶中的浓度逐渐增加到67小时时的最大平均值为45毫克/千克。随后，多拉菌素残留逐渐下降，平均残留量在523小时（22天）时低于定量限（LOQ）。再次治疗后，多拉菌素残留增加到56小时时的最大平均值为53毫克/千克。残留浓度然后在再次治疗后的237小时（10天）下降到平均值为25毫克/千克。注射治疗的残留物在任何给定时间点都一致高于涂覆制剂治疗的残留物。牛奶脂肪分析是在治疗后第1天、第4天和第10天的早晨挤奶时收集的样本进行的。这些时间点的牛奶脂肪中多拉菌素残留的平均浓度分别为557毫克/千克、1036毫克/千克和354毫克/千克。牛奶脂肪浓度因子分别为24、24.2和23.4。

The third study determined the residue depletion profile of doramectin following the subcutaneous administration of doramectin formulation at 0.23 mg/kg bw in lactating cattle, followed by retreatment at the same dose 56 days later. ... Doramectin concentrations in milk increased gradually to a maximum mean value of 45 mg/kg at 67 hr. Subsequently, doramectin residues gradually declined, with mean residues below LOQ at 523 hr (22 days). After re-treatment, doramectin residues increased to a maximum mean value of 53 mg/kg at 56 hr. Residue concentrations then decreased to a mean value of 25 mg/kg at 237 hr (10 days) after re-treatment. Residues resulting from treatment by injection were consistently higher at any given timepoint than were those resulting from treatment with the pour-on formulation. Milk fat analyses were conducted using samples collected at the morning milking on days 1, day 4 and day 10 after treatment. Mean concentrations of doramectin residues in milk fat at these time-points were 557 mg/kg, 1036 mg/kg and 354 mg/kg, respectively. Milk fat concentration factors were 24, 24.2 and 23.4, respectively.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

牛的自我舔舐行为最近被识别为局部给药伊维菌素动力学分布的决定因素。/当前研究记录了/三种局部给药的内虫杀虫剂在牛之间的转移发生和程度，这是由于异舔的结果。四组各两头的荷斯坦牛分别接受了一种多拉菌素、伊维菌素或莫西菌素的浇注剂型，或者没有治疗。然后将这些牛一起放在一个围场中。观察到至少有五头未经治疗的牛对每种局部给药的内虫杀虫剂有系统性暴露。非治疗动物中的血浆和粪便药物浓度剖面在动物之间和动物内部高度变异，有时达到治疗动物中观察到的水平。通过测量三种药物同时静脉给药后的血浆和粪便清除率来量化药物交换。多拉菌素、伊维菌素和莫西菌素的血浆清除率分别为185 + 或 - 43、347 + 或 - 77和636 + 或 - 130 ml/kg/天，粪便清除率分别代表血浆清除率的75 + 或 - 26、28 + 或 - 13和39 + 或 - 30%。未经治疗的牛摄入的药物量达到了1.3-21.3%（多拉菌素）、1.3-16.1%（伊维菌素）、2.4-10.6%（莫西菌素）的浇注剂量（500微克/千克）。所有未经治疗的牛摄入的药物总量分别代表了29%（多拉菌素）、19%（伊维菌素）和8.6%（莫西菌素）的每种药物在治疗动物背部浇注的总量的百分比。每头未经治疗的牛摄入的内虫杀虫剂累积量占浇注剂量的1.3%至27.4%。由于异舔导致的药物摄入后的口服生物利用度分别为13.5 + 或 - 9.4、17.5 + 或 - 3.5和26.1 + 或 - 11.1%对于多拉菌素、伊维菌素和莫西菌素。此处展示的药物交换程度引发了药物疗效和安全性的担忧，药物耐药性的出现，未经治疗和/或未经治疗的动物中意外高残留水平的出现以及环境负担的增加。

Self-licking behavior in cattle has recently been identified as a determinant of the kinetic disposition of topically-administered ivermectin. /The present study documents/ the occurrence and extent of transfer between cattle of three topically-administered endectocides, as a consequence of allo-licking. Four groups of two Holstein cows each received one pour-on formulation of doramectin, ivermectin, or moxidectin, or no treatment. The cows were then kept together in a paddock. Systemic exposure to each topically-administered endectocide was observed in at least five of six non-treated cattle. Plasma and fecal drug concentration profiles in non-treated animals were highly variable between animals and within an animal, and sometimes attained those observed in treated animals. Drug exchanges were quantified by measuring plasma and fecal clearances after simultaneous i.v. administration of the three drugs as a cocktail. Plasma clearances were 185 + or - 43, 347 + or - 77 and 636 + or - 130 ml/kg/day, fecal clearances representing 75 + or - 26, 28 + or - 13, and 39 + or - 30% of the plasma clearance for doramectin, ivermectin and moxidectin, respectively. The amount of drug ingested by non-treated cattle attained 1.3-21.3% (doramectin), 1.3-16.1% (ivermectin), 2.4-10.6% (moxidectin) of a pour-on dose (500 ug/kg). The total amount of drug ingested by all non-treated cattle represented 29% (doramectin), 19% (ivermectin), and 8.6% (moxidectin) of the total amount of each drug poured on the backs of treated animals. The cumulative amounts of endectocide ingested by each non-treated cow ranged from 1.3 to 27.4% of a pour-on dose. Oral bioavailability after drug ingestion due to allo-licking was 13.5 + or - 9.4, 17.5 + or - 3.5 and 26.1+ or - 11.1% for doramectin, ivermectin and moxidectin, respectively. The extent of drug exchange demonstrated here raises concerns for drug efficacy and safety, emergence of drug resistance, presence of unexpectedly high residue levels in treated and/or untreated animals and high environmental burdens.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  N,T,Xi
• 安全说明：
  S26,S33,S36/37,S45,S60,S61
• 危险类别码：
  R25
• WGK Germany：
  3
• 海关编码：
  29419090
• 危险品运输编号：
  UN2811 - class 6.1 - PG 3 - EHS - Toxic solids, organic, n.o.s., HI： all

制备方法与用途

多拉菌素简介

多拉菌素（Doramectin）是上世纪末由美国硕腾公司研制开发的新一代大环内酯类抗寄生虫药。它以环己氨羧酸为前体，通过基因重组的阿维链霉菌新菌株发酵而成，被认为是最优秀的阿维菌素族抗寄生虫药物之一。

与伊维菌素相比，多拉菌素体内血药浓度更高、消除更慢，药效维持时间也更长。其抗虫谱更为广泛，并且无过敏反应等特性，可以作为伊维菌素的良好替代品。作为一种新型的阿维菌素类抗寄生虫药物，它通过抑制神经冲动在神经肌肉间的传递使虫体麻痹并死亡。多拉菌素在体内的半衰期为5.7天，比伊维菌素（4.2天）更长。

临床实践证明，对病情轻者建议使用300微克/公斤体重的剂量，而对病情重者则可采用400微克/公斤体重的剂量。

化学结构

多拉菌素属于阿维菌素家族的大环内酯类抗生素。其分子结构与伊维菌素类似，但具有独特的生物活性和药理作用。多拉菌素的化学结构使其在NMRI小鼠感染模型中表现出抗曼氏链球菌的效果。

体内研究

体内实验显示，给S.mansoni感染的小鼠注射10毫克/千克体重的多拉菌素后，可显著降低虫体负担达60.1%。这些数据表明多拉菌素在体内具有强大的抗寄生虫效果。

使用注意事项

1. 多拉菌素性质不稳定，在阳光下会迅速分解灭活，残存药物对鱼类及水生生物有毒，需注意水源保护。
2. 浇泼剂使用后6小时内避免雨淋。
3. 慎用于犬类。
4. 本品应置于儿童接触不到的地方，并在操作时避免进食或吸烟。操作后要洗手。
5. 避免对鱼类及水生生物造成毒性影响，注意保护水资源。
6. 牛的休药期为35天，猪的休药期为24天。

生物活性

多拉菌素是伊维菌素的一种衍生物，具有显著的抗寄生虫效果。在NMRI小鼠感染模型中展现出对抗曼氏链球菌的作用。