(2S,3R,4S)-4-[(2S,7S,8R,9S)-2-[(2R,5R)-5-ethyl-5-[(2R,3S,5S)-5-[(2S,3S,5R,6R)-6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]oxolan-2-yl]-7-hydroxy-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-3-methoxy-2-methylpentanoic acid

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: (2S,3R,4S)-4-[(2S,7S,8R,9S)-2-[(2R,5R)-5-ethyl-5-[(2R,3S,5S)-5-[(2S,3S,5R,6R)-6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]oxolan-2-yl]-7-hydroxy-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-3-methoxy-2-methylpentanoic acid
• 化学式: C₃₆H₆₂O₁₁
• 分子量: 670.9
• InChiKey: GAOZTHIDHYLHMS-ZZFHHFNXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  47
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.97
• 拓扑面积：
  153
• 氢给体数：
  4
• 氢受体数：
  11

ADMET

代谢

单烯霉素是一种在兽医实践中广泛用作球虫抑制剂和生长促进剂的离子载体抗生素，对其氧化代谢进行了研究，研究对象包括马、猪、肉鸡、牛和大鼠的肝微粒体制剂。通过测量释放的甲醛的量来评估，单烯霉素的O-脱甲基化速率在所有物种中几乎相同，但总单烯霉素代谢，通过高效液相色谱（HPLC）方法测量底物消失速率来估计，牛中最高，大鼠、肉鸡和猪中居中，马中最低。当以转化数（每分钟每纳米摩尔细胞色素P450-1代谢的单烯霉素纳米摩尔数）表示时，催化效率（肉鸡>>牛>>猪≈大鼠>马）被发现与已知的不同物种对离子载体毒性影响的易感性差异呈负相关，这种差异的特点是马的口服LD50为2-3 mg/kg体重，牛为50-80 mg/kg体重，肉鸡为200 mg/kg体重。肉鸡和牛的微粒体也显示出对两种P450 3A依赖性底物（红霉素和三乙酰奥兰多霉素）的催化效率最高，并且与抗大鼠P450 3A1/2抗体交叉反应的蛋白的免疫检测水平最高。

The oxidative metabolism of monensin, an ionophore antibiotic extensively used in veterinary practice as a coccidiostat and a growth promoter, was studied in hepatic microsomal preparations from horses, pigs, broiler chicks, cattle and rats. As assayed by the measurement of the amount of the released formaldehyde, the rate of monensin O-demethylation was nearly of the same order of magnitude in all species, but total monensin metabolism, which was estimated by measuring the rate of substrate disappearance by a high-performance liquid chromatography (HPLC) method, was highest in cattle, intermediate in rats, chicks and pigs, and lowest in horses. When expressed as turnover number (nmol of metabolized monensin/min nmol cytochrome P450-1), the catalytic efficiency (chick >> cattle >> pig approximately rat > horse) was found to correlate inversely with the well known interspecies differences in the susceptibility to the toxic effects of the ionophore, which is characterized by an oral LD50 of 2-3 mg/kg bodyweight (bw) in horses, 50-80 mg/kg bw in cattle and 200 mg/kg bw in chicks. Chick and cattle microsomes also displayed both the highest catalytic efficiency toward two P450 3A dependent substrates (erythromycin and triacetyloleandomycin) and the highest immunodetectable levels of proteins cross-reacting with anti rat P450 3A1/2. ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

单烯霉素的O-脱甲基化在用苯巴比妥处理的鼠的微粒体中比未经处理的鼠更大，并且依赖于还原型烟酰胺腺嘌呤二核苷酸磷酸（NADPH），这表明单烯霉素是细胞色素P450（CYP）酶的底物。单烯霉素的氧化代谢至少部分通过CYP3A发生，因为用CYP3A的化学诱导剂处理鼠肝微粒体会显著增加单烯霉素的O-脱甲基化。有人推测，单烯霉素和其他CYP3A底物之间的竞争可能解释了在几种家养动物中联合给予单烯霉素和其他化疗药物后发生的意外中毒，因为在其他CYP3A底物存在的情况下，单烯霉素的代谢在鼠中显著降低。

The O-demethylation of monensin is greater in microsomes from phenobarbital-treated rats than in untreated rats and is dependent on reduced nicotinamide adenine dinucleotide phosphate (NADPH), suggesting that monensin is a cytochrome P450 (CYP) enzyme substrate. The oxidative metabolism of monensin appears to occur at least in part by CYP3A, since treatment of rat hepatic microsomes with chemical inducers of CYP3A significantly increased monensin O-demethylation. It has been speculated that competition between monensin and other CYP3A substrates may explain accidental poisonings that have occurred in several domestic species following coadministration of monensin and other chemotherapeutic agents, since monensin metabolism is significantly decreased in the presence of other CYP3A substrates in rats.

来源:Hazardous Substances Data Bank (HSDB)

代谢

莫能菌素代谢物主要来自于离子载体骨架上甲氧基团的O-脱甲基化以及/或在多个位置的羟基化。尽管很难获得足够的莫能菌素代谢物来测试活性，但是通过大鼠肝脏微粒体产生的四种代谢物，包括莫能菌素生产的一个副产品（O-去甲基莫能菌素），已经被测试，并且与母化合物相比，它们的抗菌、抗球虫、细胞毒性、强心剂和离子载体活性至少降低了10到20倍，这表明代谢作用消除了莫能菌素的大部分生物活性。

Monensin metabolites result mainly from O-demethylation at the methoxylic group and/or hydroxylation at several places on the ionophore backbone. ... Although it is difficult to obtain sufficient monensin metabolites to test activity, four metabolites generated by rat liver microsomes, including a by-product of monensin production (O-desmethylmonensin), have been tested and have at least 10- to 20-fold less antibacterial, anticoccidial, cytotoxic, cardiotonic and ionophoric activity than the parent compound, indicating that metabolism eliminates most of the biological activity of monensin.

来源:Hazardous Substances Data Bank (HSDB)

代谢

莫能菌素在肝脏中广泛代谢，产生了超过50种不同的代谢物，这些代谢物已在鸡、牛、大鼠、猪、狗、火鸡、羊和马的肝脏、胆汁和粪便中被检测到。在大多数物种（鸡、大鼠、狗、火鸡和猪）中，少于10%的莫能菌素以原形化合物排出，而在犊牛的一项研究中表明，粪便中识别出的(14)C有50-68%是未代谢的莫能菌素。这种在不同物种中代谢的莫能菌素量的差异可能是由于分子在不同物种中的吸收差异造成的。通过高效液相色谱(HPLC)分析方法测量底物消失速率来估算的总微粒体莫能菌素代谢率在牛中最高，在大鼠、鸡和猪中居中，在马中最低。尽管存在定量差异，实验室和非实验室动物物种之间的代谢物模式在质量上是相似的。没有单一的代谢物占据主导地位。

Monensin is extensively metabolized in the liver, producing more than 50 different metabolites that have been detected in the liver, bile and faeces of chickens, cattle, rats, pigs, dogs, turkeys, sheep and horses. In most species (chickens, rats, dogs, turkeys and pigs), less than 10% of monensin is excreted as the parent compound, whereas a study in calves indicated that 50-68% of the (14)C identified in the feces was unmetabolized monensin. This difference in amount of metabolized monensin may have been a result of differences in absorption of the molecule in different species. Total microsomal monensin metabolism, estimated by measuring the rate of substrate disappearance by a high-performance liquid chromatographic (HPLC) analytical method, is highest in cattle, intermediate in rats, chickens and pigs, and lowest in horses. The pattern of metabolites is qualitatively similar between laboratory and non-laboratory animal species, although quantitative differences exist. No single metabolite dominates the metabolic profile.

来源:Hazardous Substances Data Bank (HSDB)

代谢

单钠莫能菌素在人类肝脏微粒体的代谢已与马和狗的微粒体中的代谢进行了比较。来自多个捐赠者（男女、白人、西班牙裔和非裔美国人，年龄15-66岁）的混合人微粒体样本、混合狗微粒体样本以及来自单一捐赠者的马微粒体与0.5、1和10微克/毫升单钠莫能菌素在存在或不存在NADPH的情况下进行孵化。在0、5、10、20、40和60分钟时，通过液相色谱/质谱（LC-MS）分析检查了代谢物谱。单钠莫能菌素在所有物种中按一级动力学代谢，并且代谢是广泛的（60分钟时为93-99%）。人类中单钠莫能菌素的转化率与狗相似，而在马中的转化率仅为狗和人类的10%。

The metabolism of monensin sodium in human liver microsomes has been compared with metabolism in the microsomes of horses and dogs. A pooled human microsomal sample from multiple donors (male and female, Caucasian, Hispanic and African American, 15-66 years old), pooled dog microsome sample and equine microsomes from a single donor were incubated with 0.5, 1 and 10 ug monensin/mL in the presence or absence of NADPH. The metabolite profiles were examined at 0, 5, 10, 20, 40 and 60 min by liquid chromatography/mass spectrometry (LC-MS) analysis. Monensin was metabolized by first-order kinetics in all species, and metabolism was extensive (93-99% by 60 min). The turnover of monensin in humans was similar to that in dogs, whereas the turnover in horses was only 10% of that in dogs and humans.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

进行了一项实验，以评估莫能菌素（150 mg/kg）与生长促进剂（GPs）锌杆菌肽（BAC，50 mg/kg）、维吉尼霉素（VIR，25 mg/kg）和阿伏帕星（AVO，20 mg/kg）从7至28日龄期间喂养对肉鸡性能、饲料营养利用率、去毛去内脏胴体（DEC）产量和各种器官大小的影响。还确定了在不含莫能菌素的饲料中添加GPs至49日龄对性能和胴体的影响。莫能菌素从7至28日龄期间显著（P < 0.05）降低了采食量、体重增量和饲料效率。没有任何一种GPs能够抵消这些影响。然而，AVO略微改善了这些影响。AVO还显著增加了7至28日龄期间的采食量，并提高了增重和饲料效率，但在28至49日龄或7至49日龄期间则没有影响。VIR和BAC在任一日龄期间对性能都没有影响。莫能菌素对饲料干物质、脂肪或能量的利用率没有影响，但显著降低了氮的利用率。AVO提高了氮和脂肪的利用率，并增加了饲料的AME(n)含量。VIR也增加了AME(n)含量。这些营养物质的利用率并未受到莫能菌素与GPs之间相互作用的影响。莫能菌素在31日龄时对DEC产量或相对肝脏大小没有影响。它显著增加了小肠（SI）的相对长度并降低了其特定重量。AVO在31日龄时显著提高了产量，但在53日龄时没有影响。BAC和VIR对此变量没有影响。在两个年龄阶段，AVO和VIR（但不是BAC）显著减少了SI的大小、长度和特定重量。我们的结论是：BAC、VIR和AVO并不能抵消莫能菌素的毒性作用。GPs在提高性能方面的效果随着年龄的增长而减少甚至消失，而它们在减少SI大小方面的效果在49日龄的鸡中仍然明显。

An experiment was carried out with male broiler chicks to evaluate the combined effect of monensin (150 mg/kg) & the growth promoters (GPs) Zn bacitracin (BAC, 50 mg/kg), virginiamycin (VIR, 25 mg/kg) & avoparcin (AVO, 20 mg/kg) fed from 7 to 28 days of age on performance, utilization of dietary nutrients, yield of defeathered eviscerated carcases (DEC) & size of various organs. The effect of the GPs in the monensin-unsupplemented diets fed up to 49 d of age on performance & carcase was also determined. Monensin significantly (P < 0.05) depressed food intake, weight gain & food efficiency from 7 to 28 d of age. None of the GPs was able to counteract these effects. However, AVO slightly ameliorated them. AVO also significantly increased food intake & improved gain & food efficiency during 7 to 28, but not 28 to 49 or 7 to 49 d of age. VIR & BAC did not affect performance in either age period. Monensin did not affect the utilisation of dietary dry matter, fat or energy, but it significantly decreased nitrogen utilisation. AVO improved nitrogen & fat utilisation & increased dietary AME(n) content. AME(n) was also increased by VIR. The utilisation of these nutrients was not affected by the interactions between monensin & the GPs. Monensin did not affect yield of the DEC or the relative liver size at 31 d of age. It significantly increased the relative length of the small intestine (SI) & decreased its specific weight. AVO significantly increased yield at 31, but not at 53 d of age. BAC & VIR did not affect this variable. AVO & VIR, but not BAC, at both age periods reduced, at times significantly, the size, length & specific weight of the SI. Our conclusions: BAC, VIR & AVO do not counteract the toxic effect of monensin. The effect of GPs in improving performance decreases & even disappears with age, while their effect in reducing the size of the SI is still evident in 49 day old birds.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在这项研究中，共同给予离子载体类药物蒙纳米斯并没有改变恩诺沙星或诺氟沙星的血药水平。

In this study, co-admin of the ionophore monensin was not shown to alter blood levels of enrofloxacin or norfloxacin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

研究了莫能菌素和泰妙菌素在大鼠体内的毒性相互作用特性。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，分别研究了莫能菌素和泰妙菌素的效果（莫能菌素按10、30和50毫克/千克体重，泰妙菌素按40、120和200毫克/千克体重）。在第二阶段，同时给药这两种化合物以研究毒性相互作用（莫能菌素10毫克/千克和泰妙菌素40毫克/千克体重）。结果表明，莫能菌素在大鼠体内的剂量为30和50毫克/千克时具有毒性。泰妙菌素在剂量达到200毫克/千克时仍能良好耐受。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50毫克/千克的剂量下引起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，肝脏出现了轻微的影响（仅限雌性），心肌出现了水样变性和骨骼肌的空泡变性。在骨骼肌中看到的改变比单独给予50毫克/千克莫能菌素后看到的更加明显。

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 bw, 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 administration, 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 administration 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 administration of 50 mg/kg monensin alone.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

培养的大鼠肝细胞被处理了氰化钾，细胞色素氧化酶的抑制剂；戊内酰胺，K+离子载体；碳酰氰化物m-氯苯基腙（CCCP），质子载体；以及ATP合成酶抑制剂寡霉素。这些试剂对细胞活性的影响与ATP含量的变化和线粒体去能化有关。每个抑制剂都使ATP含量减少了90%以上。除了寡霉素外的所有试剂在4小时内杀死了细胞。除了寡霉素，用[3H]三苯甲基磷测量到的线粒体膜电位每种试剂都崩溃了。莫纳森，H+/Na+离子载体，增强了氰化物和CCCP的毒性，而戊内酰胺的毒性降低了。用荧光探针2',7'-双羧基乙基-5,6-羧基荧光素测量了氰化物和莫纳森对培养肝细胞细胞质pH的影响。氰化物迅速酸化了细胞质，加入10微莫纳森导致细胞质迅速碱化。将培养液的pH从7.4降低到6.6和6.0防止了氰化物单独以及氰化物存在莫纳森时的细胞杀伤。然而，莫纳森或