monensin

• 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: monensin
• 英文别名: rumensin；(3R,4S)-4-[(2S,5R,7S,8R,9S)-2-[(2R,5S)-5-ethyl-5-[(2R,3S,5R)-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: 670.882
• InChiKey: GAOZTHIDHYLHMS-QPJULDDXSA-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。本研究探讨了单烯霉素在马、猪、肉鸡、牛和大鼠的肝微粒体中的氧化代谢。通过测定释放的甲醛的量来评估，发现所有物种的单烯霉素O-脱甲基速率几乎处于相同的数量级，但总单烯霉素代谢（通过高效液相色谱法测量底物消失速率来估计）在牛中最高，在大鼠、肉鸡和猪中居中，在马中最低。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）被发现与物种对离子载体毒性作用的易感性差异呈反比关系，这种差异通过口服LD50值来表示，马为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）的最高催化效率，以及与抗大鼠P450 3A1/2抗体交叉反应的最高免疫可检测蛋白水平。

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

单烯菌素在经过苯巴比妥处理的鼠肝微粒体中的O-脱甲基作用比未经处理的鼠要大，并且这一过程依赖于还原型烟酰胺腺嘌呤二核苷酸磷酸（NADPH），这表明单烯菌素是细胞色素P450（CYP）酶的底物。单烯菌素的氧化代谢至少部分是通过CYP3A进行的，因为用CYP3A的化学诱导剂处理鼠肝微粒体会显著增加单烯菌素的O-脱甲基作用。有人推测，单烯菌素与其他CYP3A底物之间的竞争可能解释了在几种家养动物中同时给予单烯菌素和其他化疗药物后发生的意外中毒事件，因为在大鼠中，当存在其他CYP3A底物时，单烯菌素的代谢会显著减少。

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（包括莫能菌素生产过程中的一个副产品O-去甲基莫能菌素）已经过测试，它们的抗菌、抗球虫、细胞毒性、强心剂和离子载体活性至少比母化合物低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

• 毒性总结

识别和使用：莫能菌素是一种多醚羧酸离子载体抗生素。莫能菌素是由四种类似物A、B、C和D组成的混合物，其中莫能菌素A是主要成分（98%）。根据纯化的方法，莫能菌素可以以菌丝体、结晶体和再结晶体的形式存在。它用于治疗家禽（鸡、火鸡和鹌鹑）和反刍动物（牛、羊和山羊）的球虫病。莫能菌素还用于控制牛的酮病和膨胀，并作为牛和羊的生长促进剂饲料添加剂。莫能菌素主要对革兰氏阳性细菌有效。人类暴露和毒性：一名17岁的男孩在摄入莫能菌素钠后11天出现肌红蛋白尿、肾衰竭和死亡。在另一例中，一名患者服用了比牛致死剂量高三倍的莫能菌素，出现了与兽医医学中报道的临床表现相似的病状。出现了早期的极其严重的横纹肌溶解，随后是急性肾衰竭、心衰和死亡。尸检时观察到的主要变化是广泛的骨骼肌坏死、心肌水平的补体沉积、肺水肿和急性管状损伤。动物研究：在成熟的猕猴中研究了急性毒性。将成对的猴子通过灌胃给予单次剂量的20、40或60毫克/千克体重莫能菌素，并监测7天。所有动物在给药后24小时内都存活并出现腹泻。成年山羊通过胃灌胃每天连续五天给予13.5毫克/千克体重的钠莫能菌素。莫能菌素暴露引起了腹泻、心动过速和瘤胃运动以及体温的降低。在一项吸入暴露研究中，大鼠暴露于正常空气或含有平均浓度为79毫克/立方米的颗粒状菌丝体莫能菌素钠的空气，持续2周（每天1小时，每周5天）。在研究的第二周，10只处理过的雌性中有9只出现厌食和体重下降。在两只雄性和两只雌性中观察到轻微的局部骨骼肌炎，但在对照组中没有。在雄性大鼠中观察到多灶性心肌变化。在一项亚慢性研究中，将雄性和雌性小鼠喂食含有0、37.5、75、150或300毫克/千克菌丝体莫能菌素钠的饮食，持续3个月。所有剂量组都出现了剂量依赖性的体重增加下降。在研究结束时，下降幅度从最低剂量组雌性和雄性分别的27%和21%到最高剂量组两性的99%。在一项慢性毒性研究中，将雄性和雌性大鼠维持在一个含有25、56或125毫克/千克结晶莫能菌素钠的饮食中，而对照组大鼠在2年内接受正常饮食。在125毫克/千克饮食中的动物的体重和体重增加显著降低，而在中间剂量组的大鼠在头4个月内暂时降低。在处理和未处理的动物中观察到了良性肿瘤和恶性肿瘤，但没有发现莫能菌素管理与肿瘤类型或严重程度有关。莫能菌素对马有毒。临床表现为心动过速和心律失常、呻吟、不协调、出汗、躺卧和四肢划水样动作。尸检的主要发现是在骨骼肌和心肌。研究了大鼠在发育期间暴露于莫能菌素的影响。将雌性大鼠分成几组，分别给予0、100或300毫克/千克的莫能菌素，直到交配前体重达到185克，并在怀孕和哺乳期间继续给药。在最高剂量组中，雌性体重在治疗8天后显著下降。最高剂量组雄性和雌性幼崽的体重从出生后第10天降至出生后第21天。低剂量组的雄性后代仅在出生后第21天出现体重下降。在幼崽中没有检测到外部的畸形迹象。还进行了一项研究，以探索莫能菌素，一种强大的高尔基体干扰剂对雄性生育的影响。将雄性大鼠给予2.5、5和10毫克/千克体重的莫能菌素。动物在治疗67天后被处死。电子显微镜下的发现，如膜破裂、肿胀和高尔基体的解体，强烈提示莫能菌素干扰了精原细胞中高尔基体的功能。来自精子数量和活力以及生育研究和产生的窝大小的数据进一步指出了莫能菌素在雄性大鼠中的抗生育效果。致突变性试验为阴性。

IDENTIFICATION AND USE: Monensin is a polyether carboxylic ionophore antibiotic. Monensin is a mixture of four analogues, A, B, C and D, with monensin A being the major component (98%). Depending on the method of purification, monensin can exist in mycelial, crystalline and recrystallized forms. It is used for the treatment of coccidiosis in poultry (chickens, turkeys and quail) and ruminants (cattle, sheep and goats). Monensin is also used to control ketosis and bloat in cattle and as a growth promoter feed additive in cattle and sheep. Monensin is mainly effective against Gram-positive bacteria. HUMAN EXPOSURE AND TOXICITY: 17 year-old boy who developed myoglobinuria, renal failure and death 11 days after ingesting sodium monensin. In another case, a patient took a dose of monensin three times higher than a dose considered lethal for cattle and developed a clinical picture similar to that reported in veterinary medicine. There was an early and extremely severe rhabdomyolysis followed by acute renal failure, heart failure, and death. The main changes observed at autopsy were extensive skeletal muscle necrosis, complement deposition at the myocardial level, pulmonary edema, & acute tubular damage. ANIMAL STUDIES: Acute toxicity was examined in mature rhesus monkeys. Pairs of monkeys were exposed to a single dose of 20, 40 or 60 mg monensin/kg bw by gavage and were monitored for 7 days. All animals survived and developed diarrhea within 24 hr after dosing. Adult goats were administered sodium monensin, 13.5 mg kg (-1), daily for five consecutive days via gastric gavage. Monensin exposure caused diarrhea, tachycardia and reduction in ruminal movements and body temperature. In an inhalational exposure study, rats were exposed to either normal air or air containing particulate mycelial monensin sodium at a mean concentration of 79 mg/cu m for 2 weeks (1 hr/day, 5 days/week). Nine of 10 treated females became anorexic and lost weight during the 2nd week of the study. Slight focal myositis of the skeletal muscle was seen in two males and two females but non