妥布霉素 - CAS号 32986-56-4

物化性质

熔点：

178 °C
比旋光度：

D20 +129° (c = 1 in water)
沸点：

570.01°C (rough estimate)
密度：

1.3458 (rough estimate)
溶解度：

H2O：50 mg/mL，清澈，淡黄色
物理描述：

Solid
颜色/状态：

White to off-white powder
蒸汽压力：

2.37X10-21 mm Hg at 25 °C (est)
稳定性/保质期：

Stable under recommended storage conditions.
旋光度：

Specific optical rotation: +129 deg at 20 °C/D (c = 1 in water)
分解：

Hazardous decomposition products formed under fire conditions - Carbon oxides, nitrogen oxides (NOx).
解离常数：

pKb1 = 8.6; pKb2 = 8.8; pKb3 = 9.0 (amines) (est)

计算性质

辛醇/水分配系数(LogP)：

-6.2
重原子数：

32
可旋转键数：

6
环数：

3.0
sp3杂化的碳原子比例：

1.0
拓扑面积：

268
氢给体数：

10
氢受体数：

14

ADMET

代谢

托布霉素不易被代谢。

Tobramycin is not appreciably metabolized.

来源:DrugBank

代谢

氨基糖苷类药物不被代谢，主要通过肾小球滤过作用以原形在尿液中排出。/氨基糖苷类/

Aminoglycosides are not metabolized and are excreted unchanged in the urine primarily by glomerular filtration. /Aminoglycosides/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

毒性总结

识别和使用：妥布霉素是一种氨基糖苷类抗生素。人类暴露和毒性：在接受妥布霉素治疗的病人中，罕见报道了严重的过敏反应，包括过敏性休克和皮肤病反应，如剥脱性皮炎、中毒性表皮坏死松解症、多形性红斑和史蒂文斯-约翰逊综合症。虽然罕见，但已有死亡报告。已经注意到对第八神经的耳蜗和听觉分支的不利影响，特别是在接受高剂量或长期治疗的病人中，那些以前接受过耳毒性药物治疗的人，以及在脱水情况下。症状包括头晕、眩晕、耳鸣、耳朵轰鸣和听力损失。听力损失通常是不可逆的，最初表现为高音听力下降。已经报道了肾功能变化，表现为血尿素氮、非蛋白氮和血清肌酐升高以及少尿、圆柱尿和蛋白尿增加，特别是在有肾功能损害病史的病人中，他们接受的治疗时间更长或剂量高于推荐剂量。即使最初肾功能正常的病人也可能会出现不良反应。几乎所有的抗菌药物使用中都报告了与难辨梭菌相关的腹泻，包括注射用妥布霉素，病情严重程度可能从轻度腹泻到致命性结肠炎不等。动物研究：将5%的妥布霉素眼药水应用于兔眼仅引起轻微的结膜红斑。然而，0.3%的妥布霉素眼药水干扰了兔角膜内皮的愈合。产生耳蜗毒性的平均用药天数，表现为平衡反射受损或运动失调，在给予妥布霉素的猫中为41到61天。对耳蜗的组织学检查显示，大多数给予40和80 mg/kg妥布霉素的猫耳蜗中的毛细胞和支持感觉结构发生了变性。在器官发生期，给予高剂量的妥布霉素（30或60 mg/kg/天，连续10天）后，观察到孕鼠及其胎儿的肾毒性。与剂量相关的胎儿肾毒性包括近端小管细胞的颗粒化和肿胀、不良的肾小球分化和肾小球密度增加。

IDENTIFICATION AND USE: Tobramycin is aminoglycoside antibiotic. HUMAN EXPOSURE AND TOXICITY: Serious allergic reactions including anaphylaxis and dermatologic reactions including exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, and Stevens-Johnson Syndrome have been reported rarely in patients on tobramycin therapy. Although rare, fatalities have been reported. Adverse effects on both the vestibular and auditory branches of the eighth nerve have been noted, especially in patients receiving high doses or prolonged therapy, in those given previous courses of therapy with an ototoxin, and in cases of dehydration. Symptoms include dizziness, vertigo, tinnitus, roaring in the ears, and hearing loss. Hearing loss is usually irreversible and is manifested initially by diminution of high-tone acuity. Renal function changes, as shown by rising BUN, NPN, and serum creatinine and by oliguria, cylindruria, and increased proteinuria, have been reported, especially in patients with a history of renal impairment who are treated for longer periods or with higher doses than those recommended. Adverse renal effects can occur in patients with initially normal renal function. Clostridium difficile associated diarrhea has been reported with use of nearly all antibacterial agents, including Tobramycin for Injection, USP, and may range in severity from mild diarrhea to fatal colitis. ANIMAL STUDIES: Tobramycin applied as 5% eyedrops to rabbit eyes caused only mild conjunctival erythema. However, 0.3% tobramycin eyedrops interfered with healing of rabbit corneal endothelium. The mean number of dose days required to produce vestibulotoxic effects, demonstrated by impaired righting reflex or locomotor ataxia, was from 41 to 61 in cats dosed with tobramycin. Histologic examination of the cochleae revealed degeneration of the hair cells and supporting sensory structures in the majority of cats dosed with tobramycin at 40 and 80 mg/kg. Renal toxicity was observed in pregnant rats and their fetuses after maternal administration of high doses of tobramycin, 30 or 60 mg/kg/day fo 10 days, during organogenesis. The dose-related fetal renal toxicity consisted of granularity and swelling of proximal tubule cells, poor glomerular differentiation, and increased glomerular density.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

肝毒性

静脉和肌肉注射妥布霉素通常不会增加血清转氨酶或胆红素升高的发生率。只有少数关于包括妥布霉素在内的氨基糖苷类治疗引起的急性肝损伤和黄疸的孤立病例报告，而且并非所有报告都非常有说服力。肝损伤通常是混合型的，但可以发展为胆汁淤积性肝炎。发病潜伏期很短，发生在1到3周内，通常伴有皮疹、发热，有时伴有嗜酸性粒细胞增多。恢复通常发生在1到2个月内，没有描述慢性损伤。在药物引起的肝病和急性肝衰竭的大型病例系列中并未提到氨基糖苷类药物；因此，如果发生的话，由妥布霉素引起的肝损伤是罕见的。

Intravenous and intramuscular therapy with tobramycin is usually associated with no increase in rates of serum aminotransferase or bilirubin elevations. Only isolated case reports of acute liver injury with jaundice have been associated with aminoglycoside therapy including tobramycin, not all of which are very convincing. The hepatic injury is typically mixed but can evolve into a cholestatic hepatitis. The latency to onset is rapid, occurring within 1 to 3 weeks and is typically associated with skin rash, fever and sometimes eosinophilia. Recovery typically occurs within 1 to 2 months and chronic injury has not been described. Aminoglycosides are not mentioned in large case series of drug induced liver disease and acute liver failure; thus, hepatic injury due to tobramycin is rare if it occurs at all.

来源:LiverTox

毒理性

在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用概述：妥布霉素在母乳中的排泄量很少。新生儿显然会吸收少量其他氨基糖苷类药物，但在典型的每日三次剂量下，血清水平远低于治疗新生儿感染时达到的水平，因此妥布霉素的系统影响不太可能发生。年龄较大的婴儿吸收的妥布霉素会更少。由于在多次每日剂量方案中，母乳中妥布霉素水平的变异性很小，因此在与剂量相关的哺乳时机上减少婴儿暴露几乎没有或没有好处。对于单日剂量方案，尚无数据。监测婴儿可能出现的影响胃肠道菌群的情况，如腹泻、念珠菌病（例如，鹅口疮、尿布疹）或罕见的情况下，粪便中出现血液，提示可能存在抗生素相关性结肠炎。母亲使用含有妥布霉素的耳滴或眼滴对哺乳婴儿几乎没有或没有风险。一个由欧洲、澳大利亚和新西兰的呼吸专家组成的小组发现，吸入妥布霉素与哺乳是相容的。 ◉ 对哺乳婴儿的影响：一名婴儿在产后第4个月之前一直母乳喂养（喂养程度未说明）。在2个月大时，他的母亲因囊性纤维化加重而接受了为期2周的妥布霉素150毫克，每日三次加美罗培南的治疗。在母亲治疗期间，婴儿的大便模式没有变化，在6个月大时肾功能正常。 ◉ 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:Tobramycin is poorly excreted into breastmilk. Newborn infants apparently absorb small amounts of other aminoglycosides, but serum levels with typical three times per day dosages are far below those attained when treating newborn infections and systemic effects of tobramycin are unlikely. Older infants would be expected to absorb even less tobramycin. Because there is little variability in the milk tobramycin levels during multiple daily dose regimens, timing breastfeeding with respect to the dose is of little or no benefit in reducing infant exposure. Data are not available with single daily dose regimens. Monitor the infant for possible effects on the gastrointestinal flora, such as diarrhea, candidiasis (e.g., thrush, diaper rash) or rarely, blood in the stool indicating possible antibiotic-associated colitis. Maternal use of an ear drop or eye drop that contains tobramycin presents little or no risk for the nursing infant. A task force respiratory experts from Europe, Australia and New Zealand found that inhaled tobramycin is compatible with breastfeeding. ◉ Effects in Breastfed Infants:An infant was breastfed (extent not stated) until the 4th month postpartum. At 2 months of age, his mother was given a 2-week course of tobramycin 150 mg three times daily plus meropenem for a cystic fibrosis exacerbation. infant displayed no change in stool pattern during the maternal treatment and had normal renal function at 6 months of age. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

相互作用

同时和/或连续使用氨基糖苷类和其他具有神经毒性、耳毒性和肾毒性的系统性、口服或局部药物（例如，其他氨基糖苷类、阿昔洛韦、两性霉素B、杆菌肽、卷曲霉素、某些头孢菌素、粘菌素、顺铂、甲氧氟烷、多粘菌素B、万古霉素）可能会导致毒性相加，应尽可能避免。/氨基糖苷类/

Concomitant and/or sequential use of an aminoglycoside and other systemic, oral, or topical drugs that have neurotoxic, ototoxic, or nephrotoxic effects (e.g., other aminoglycosides, acyclovir, amphotericin B, bacitracin, capreomycin, certain cephalosporins, colistin, cisplatin, methoxyflurane, polymyxin B, vancomycin) may result in additive toxicity and should be avoided, if possible. /Aminoglycosides/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

相互作用

由于增加耳毒性风险的可能性，由于附加效应或改变的血清和组织氨基糖苷浓度，氨基糖苷类药物不应与强效利尿剂（如依他尼酸、呋塞米、尿素或甘露醇）同时使用。有人建议，某些抑制前庭源性和眩晕引起的恶心和呕吐的抗呕吐药（例如，美克洛嗪、美其金）的联合使用可能掩盖氨基糖苷类药物相关的前庭耳毒性的症状。/氨基糖苷类药物/

Because of the possibility of an increased risk of ototoxicity due to additive effects or altered serum and tissue aminoglycoside concentrations, aminoglycosides should not be given concomitantly with potent diuretics such as ethacrynic acid, furosemide, urea, or mannitol. It has been suggested that concomitant use of certain anti-emetics that suppress nausea and vomiting of vestibular origin and vertigo (e.g., dimenhydrinate, meclizine) may mask symptoms of aminoglycoside-associated vestibular ototoxicity. /Aminoglycosides/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

吸收

吸入给药的妥布霉素在囊性纤维化患者中，痰液中的药物浓度变化比血清中的更大。在单次112毫克剂量后，血清中的最高浓度（Cmax）为1.02 ± 0.53微克/毫升，在一小时内达到（Tmax），而痰液中的Cmax为1048 ± 1080微克/克。相比之下，对于300毫克剂量，血清Cmax为1.04 ± 0.58微克/毫升，同样在一小时内达到，而痰液Cmax为737 ± 1028微克/克。两个剂量的系统暴露（AUC0-12）也相似，112毫克剂量的AUC0-12为4.6 ± 2.0微克·小时/毫升，300毫克剂量的AUC0-12为4.8 ± 2.5微克·小时/毫升。当妥布霉素以112毫克每日两次的剂量连续四周给药时，给药后一小时内测得的Cmax范围从1.48 ± 0.69微克/毫升到1.99 ± 0.59微克/毫升。

Tobramycin administered by inhalation in cystic fibrosis patients showed greater variability in sputum as compared to serum. After a single 112 mg dose, the serum Cmax was 1.02 ± 0.53 μg/mL, which was reached in one hour (Tmax), while the sputum Cmax was 1048 ± 1080 μg/g. Comparatively, for a 300 mg dose, the serum Cmax was 1.04 ± 0.58 μg/mL, which was also reached within one hour, while the sputum Cmax was 737 ± 1028 μg/g. The systemic exposure (AUC0-12) was also similar between the two doses, at 4.6 ± 2.0 μg∙h/mL for the 112 mg dose and 4.8 ± 2.5 μg∙h/mL for the 300 mg dose. When tobramycin was administered over a four-week cycle at 112 mg twice daily, the Cmax measured one hour after dosing ranged from 1.48 ± 0.69 μg/mL to 1.99 ± 0.59 μg/mL.

来源:DrugBank

吸收、分配和排泄

消除途径

庆大霉素主要通过尿液以原形排出。

Tobramycin is primarily excreted unchanged in the urine.

来源:DrugBank

吸收、分配和排泄

分布容积

吸入妥布霉素在典型囊性纤维化患者中央室的表观分布容积为85.1升。

Inhalation tobramycin had an apparent volume of distribution in the central compartment of 85.1 L for a typical cystic fibrosis patient.

来源:DrugBank

吸收、分配和排泄

清除

吸入托布霉素在6至58岁的囊性纤维化患者中的表观血清清除率为14.5升/小时。

Inhaled tobramycin has an apparent serum clearance of 14.5 L/h in cystic fibrosis patients aged 6-58 years.

来源:DrugBank

吸收、分配和排泄

托布霉素在胃肠道吸收不良。

Tobramycin is poorly absorbed from the GI tract.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

危险品标志：

Xi
安全说明：

S26,S37/39

妥布霉素 | 32986-56-4

物质功能分类

分子结构分类

物化性质

计算性质

ADMET

安全信息