(1R,2S,5R,7R,8R,9R,11R,13R,14R)-8-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-9-methoxy-1,5,7,9,11,13-hexamethyl-15-[4-(4-pyridin-3-ylimidazol-1-yl)butyl]-3,17-dioxa-15-azabicyclo[12.3.0]heptadecane-4,6,12,16-tetrone | 191114-48-4

• 物质功能分类: 原料药 - 抗生素类药物 - 大环内酯类药
• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (1R,2S,5R,7R,8R,9R,11R,13R,14R)-8-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-9-methoxy-1,5,7,9,11,13-hexamethyl-15-[4-(4-pyridin-3-ylimidazol-1-yl)butyl]-3,17-dioxa-15-azabicyclo[12.3.0]heptadecane-4,6,12,16-tetrone
• CAS: 191114-48-4
• 化学式: C₄₃H₆₅N₅O₁₀
• 分子量: 812.0
• InChiKey: LJVAJPDWBABPEJ-RMNISARHSA-N

物化性质

• 熔点：
  176-188 C
• 沸点：
  966℃
• 密度：
  1.26±0.1 g/cm3(Predicted)
• 闪点：
  >110°(230°F)
• 溶解度：
  可溶于氯仿（少许）、DMSO（少许）、甲醇（少许）
• 物理描述：
  Solid
• 颜色/状态：
  White to off-white crystalline powder

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  58
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.72
• 拓扑面积：
  172
• 氢给体数：
  1
• 氢受体数：
  13

ADMET

代谢

大约70%（其中33%在系统前，37%在系统中）的口服剂量大约相等地由细胞色素P450（CYP）3A4和非CYP3A4同工酶代谢成4种主要代谢物。系统上可利用的泰利霉素以原药形式在粪便中消除（7%），在尿液中以原药形式消除（13%），并在肝脏中代谢了37%。

About 70% (33% presystemic and 37% systemic) of an oral dose is metabolized about equally by cytochrome P450 (CYP) 3A4 and non-CYP3A4 isoenzymes to 4 major metabolites. The systemically available telithromycin is eliminated in the feces as unchanged drug (7%), in urine as unchanged drug (13%), and 37% is metabolized in the liver.

来源:Hazardous Substances Data Bank (HSDB)

代谢

生物转化：肝脏；剂量的37%通过肝脏代谢。代谢约占剂量的70%。主要代谢物占AUC的12.6%，而另外三种被定量测定的代谢物占特立霉素AUC的3%或更少。

Biotransformation: Hepatic; 37% of the dose is metabolized by the liver. Metabolism accounts for approximately 70% of the dose. The main metabolite represented 12.6% of the AUC while three other metabolites quantified represented 3% or less of the AUC of telithromycin.

来源:Hazardous Substances Data Bank (HSDB)

代谢

总的来说，代谢过程约占剂量的70%。在血浆中，服用800毫克放射性标记剂量后，主要循环化合物是母化合物，占总放射性的56.7%。主要代谢物占泰利霉素AUC的12.6%。还有三种其他血浆代谢物被定量，每一种都占泰利霉素AUC的3%或更少。估计大约50%的代谢是通过CYP 450 3A4介导的，剩余的50%是CYP 450独立的。

In total, metabolism accounts for approximately 70% of the dose. In plasma, the main circulating compound after administration of an 800-mg radiolabeled dose was parent compound, representing 56.7% of the total radioactivity. The main metabolite represented 12.6% of the AUC of telithromycin. Three other plasma metabolites were quantified, each representing 3% or less of the AUC of telithromycin. It is estimated that approximately 50% of its metabolism is mediated by CYP 450 3A4 and the remaining 50% is CYP 450-independent.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

与其他大环内酯类抗生素一样，泰利霉素在治疗期间与低发生率（1%至2%）的短暂血清酶升高有关。然而，这些升高通常是暂时的，即使继续用药也会解决，并且比较药物也可能出现相似比例的血清酶升高。更重要的是，泰利霉素与严重形式的急性、临床明显肝毒性的病例有关，首次报告是在其在美国获得普遍使用批准后不久。肝损伤发病的典型潜伏期是迅速的，有些病例在治疗开始后一两天内出现，平均潜伏期为1周。肝损伤往往是突然发病，表现为乏力、虚弱、黄疸和发热。酶升高的模式通常是肝细胞型的，血清转氨酶水平可能非常高（>1000 U/L）。有报道归因于泰利霉素的轻度非黄疸性肝损伤病例，但有些病例非常严重，并伴有腹水和肝性脑病快速发展的肝衰竭。嗜酸性粒细胞增多和皮疹可能出现，但不常见。再次接触后损伤复发的病例已有描述。

As with other macrolide antibiotics, telithromycin has been associated with a low rate (1% to 2%) of transient serum enzyme elevations during therapy. These elevations, however, are usually transient and resolve even with drug continuation and a similar rate of serum enzyme elevations can occur with comparator agents. More importantly, telithromycin has been linked to severe forms of acute, clinically apparent hepatotoxicity, first reported within a short time of its general approval for use in the United States. The typical latency to onset of liver injury is rapid, some cases presenting within a day or two of initiation of therapy, the average latency being 1 week. The liver injury is often abrupt in onset with fatigue, weakness, jaundice and fever. The pattern of enzyme elevations is typically hepatocellular and serum aminotransferase levels can be quite high (>1000 U/L). Mild and anicteric cases of liver injury attributed to telithromycin have been reported, but some cases are very severe and associated with rapid development of hepatic failure with ascites and hepatic encephalopathy. Eosinophilia and rash can occur, but are not common. Recurrence of injury with reexposure has been described.

来源:LiverTox

毒理性

• 相互作用

/泰利霉素与匹莫齐特/合用是禁忌的；存在匹莫齐特水平升高的风险。

/Use of telithromycin with pimozide/ is contraindicated; risk of increased pimozide levels.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

使用替利霉素与苯巴比妥、苯妥英或圣约翰草可能会导致替利霉素的血药浓度低于治疗水平，从而失去疗效。

/Use of telithromycin with phenobarbital, phenytoin, or St. John's wort/ may result in subtherapeutic levels of telithromycin and loss of effect.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

当泰利霉素与通过CYP 3A4代谢并经历高首过效应的苯二氮䓬类药物一起给药时，其他苯二氮䓬类药物的血清水平可能会升高。

When telithromycin is administered with benzodiazepine which are metabolized by CYP 3A4 and undergo a high first-pass effect, serum levels of the other benzodiazepines may increase.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

当与泰利霉素同时使用时，可能会增加咪达唑仑的曲线下面积（AUC）；如果必要，应监测患者，并考虑调整咪达唑仑的剂量。

May increase midazolam AUC /when used concurrently with telithromycin/; patients should be monitored and dosage adjustments of midazolam should be considered if necessary.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

泰利霉素在白细胞中的浓度超过血浆中的浓度，并且从白细胞中的消除速度比从血浆中慢。泰利霉素在白细胞中的平均浓度在6小时时达到72.1微克/毫升的峰值，经过5天每天一次600毫克的重复给药后，24小时后保持在14.1微克/毫升。经过10天，每天一次600毫克的重复给药后，白细胞中的浓度在最后一次给药后48小时保持在8.9微克/毫升。

Telithromycin concentration in white blood cells exceeds the concentration in plasma and is eliminated more slowly from white blood cells than from plasma. Mean white blood cell concentrations of telithromycin peaked at 72.1 ug/mL at 6 hours, and remained at 14.1 ug/mL 24 hours after 5 days of repeated dosing of 600 mg once daily. After 10 days, repeated dosing of 600 mg once daily, white blood cell concentrations remained at 8.9 ug/mL 48 hours after the last dose.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

分布容积 - 2.9 L/kg 静脉输注后。广泛分布于全身。泰利霉素可分布到大鼠的乳汁中。

Volume of distribution - 2.9 L/kg following an intervenous infusion. Widely distributed throughout the body. Telithromycin is distributed into breast milk of rats.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

迅速吸收，年轻和老年患者的绝对生物利用度均为57%。食物不影响吸收速率和程度。单次给药后的AUC为8.25微克/小时/毫升，多次给药后的AUC为12.5微克/小时/毫升。

Rapidly absorbed, absolute bioavailability is 57% in both young and elderly patients. The rate and extent of absorption are unaffected by food. The AUC following a single dose is 8.25 ug h/mL and 12.5 ug h/mL following multiple dosing.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

系统中可用的泰利霉素通过多种途径消除，具体如下：7%的剂量通过胆汁和/或肠道分泌以原形在粪便中排出；13%的剂量通过肾脏排泄以原形在尿液中排出；而37%的剂量在肝脏中被代谢。

The systemically available telithromycin is eliminated by multiple pathways as follows: 7% of the dose is excreted unchanged in feces by biliary and/or intestinal secretion; 13% of the dose is excreted unchanged in urine by renal excretion; and 37% of the dose is metabolized by the liver.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  9
• 危险品标志：
  Xi
• 安全说明：
  S26,S36
• 危险类别码：
  R36/37/38
• RTECS号：
  KF4674500
• 危险类别：
  9

制备方法与用途

大环内酯类抗生素——泰利霉素

近年来，人们研发出一种新的大环内酯类抗生素——泰利霉素。它是林可酰胺—链阳霉素B（MLSB）家族中的第一个抗菌药物，并且是首个获准应用于临床的酮内酯类抗生素，由法国赛诺菲-安万特集团研发成功。泰利霉素具有广谱抗菌活性和较低的选择性耐药性，对肺炎链球菌及其耐青霉素和红霉素菌株、嗜血流感杆菌和莫拉汉菌均有良好疗效，其抗菌作用比阿奇霉素等大环内酯类抗生素更强。主要用于治疗呼吸道感染、支气管炎、咽炎、扁桃体炎以及肺炎等。

泰利霉素的作用机制与大环内酯类抗生素相似，主要通过直接与细菌核糖体的50s亚基结合，抑制蛋白质合成，并阻抑其翻译和装配。它还可与23s核糖体RNA的Ⅱ和Ⅴ结构区的核苷酸结合。不过，泰利霉素对野生型核糖体的结合力较红霉素和克拉霉素分别强约10倍和6倍。这种微小差异使其对细菌的耐受能力提高了20倍，并使其对大环内酯的所有耐药菌株有效。

泰利霉素口服吸收良好，口服生物利用度约为57%，食物不会影响其吸收。药物在肝脏被CYP3A4代谢为泰利醇、泰利酸、N-去甲脱氧酰胺衍生物、N-氧吡啶衍生物。半衰期（T1/2）为9.81小时，肾清除率为12.5L/h。药物通过多种途径排泄：约13%以原形从尿中排出，3%以原形从粪便中排出，代谢产物有37%从肝脏排泄。肝功能不全者，Cmax降低约20%，T1/2较正常人延长1.4倍，代谢率亦减少。在社区获得性肺炎(CAP)患者中的药动学参数平均为：Cmax为2.89 mg/L，Cmin为0.19 mg/L，AUC为13.9 mg/(L·h)。

2007年2月12日，美国食品和药物管理局宣布对赛诺菲-安万特生产的抗生素泰利霉素（又称肯立克）的药品标签作出修改，将急性细菌性鼻窦炎、慢性支气管炎的急性细菌性恶化两项适应症从说明书上移除，并提醒患者注意安全使用泰利霉素。

生物活性：Telithromycin(HMR3647)是一种可作用于社区获得性肺炎的抗生素。