(1S,2R,5R,7R,8R,9S,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: (1S,2R,5R,7R,8R,9S,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-KMPMGEDVSA-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）
• 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%由肝脏代谢。代谢约占剂量的70%。主要代谢物占AUC的12.6%，而其他三种定量代谢物占特立霉素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，占总放射活性的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，其余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)

代谢

肝脏 - 估计有50%通过CYP3A4代谢，另外50%独立于细胞色素P450代谢 消除途径：系统可利用的泰利霉素通过多种途径消除，如下所示：剂量的7%未改变通过胆汁和/或肠道分泌在粪便中排出；剂量的13%未改变通过肾脏排泄在尿液中排出；剂量的37%通过肝脏代谢。 半衰期：主要消除半衰期为2-3小时；终末消除半衰期为10小时

Hepatic - estimated 50% metabolized by CYP3A4 and 50% metabolized independent of cytochrome P450 Route of Elimination: 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. Half Life: Main elimination half-life is 2-3 hours; terminal elimination half-life is 10 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

泰利霉素通过与50S核糖体亚单位的23S rRNA的II和V结构域结合发挥作用。通过结合在II结构域，泰利霉素在存在通过改变泰利霉素V结构域结合位点介导耐药的甲基化酶（erm基因）的情况下，仍对革兰氏阳性球菌（例如肺炎链球菌）保持活性。泰利霉素还可能抑制新生的核糖体单元的组装。与红霉素A相比，泰利霉素在红霉素敏感生物体中的结合亲和力高出10倍，在 macrolide-resistant 耐药菌株中高出25倍。这种增加的结合亲和力可能是由泰利霉素的C11-12碳酸酯侧链赋予的。该侧链似乎在存在由V结构域改变介导的耐药时，保持与II结构域的结合。

Telithromycin acts by binding to domains II and V of 23S rRNA of the 50S ribosomal subunit. By binding at domain II, telithromycin retains activity against gram-positive cocci (e.g., <i>Streptococcus pneumoniae</i>) in the presence of resistance mediated by methylases (erm genes) that alter the domain V binding site of telithromycin. Telithromycin may also inhibit the assembly of nascent ribosomal units. Compared to erythromycin A, telithromycin binds to the 23S rRNA with 10 times greater affinity in erythromycin-susceptible organisms and 25 times greater affinity in macrolide-resistant strains. This increased binding affinity may be conferred by the C11-12 carbamate side chain of telithromycin. The side chain appears to maintain binding at domain II in the presence of resistance mediated by alterations in domain V.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类无致癌性（未列入国际癌症研究机构IARC清单）。

No indication of carcinogenicity to humans (not listed by IARC).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：由于没有关于母乳喂养期间使用泰利霉素的已发表经验，可能更倾向于选择另一种药物，特别是在哺乳新生儿或早产儿时。 ◉ 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发表信息。 ◉ 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发表信息。

◉ Summary of Use during Lactation:Because there is no published experience with telithromycin during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ 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

• 暴露途径

绝对生物利用度大约为57%。口服给药后0.5-4小时达到最大浓度。食物摄入不影响吸收。

Absolute bioavailability is approximately 57%. Maximal concentrations are reached 0.5 - 4 hours following oral administration. Food intake does not affected absorption.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 症状

最常见的副作用是胃肠道方面的，包括腹泻、恶心、腹痛和呕吐。头痛和味觉异常也有发生。较少见的副作用包括心悸、视力模糊和皮疹。[维基百科]

Most common side-effects are gastrointestinal, including diarrhea, nausea, abdominal pain and vomiting. Headache and disturbances in taste also occur. Less common side-effects include palpitations, blurred vision and rashes. [Wikipedia]

来源:Toxin and Toxin Target Database (T3DB)

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。在每日一次重复给药600毫克5天后，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，并在24小时后保持在14.1微克/毫升。在每日一次重复给药600毫克10天后，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

系统性地提供的泰利霉素通过多种途径被消除，如下所示：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。

文献信息

• COMPOSITIONS AND MEANS FOR DIAGNOSING MICROBIAL INFECTIONS
  申请人：Statens Serum Institut

  公开号：EP2181330B1

  公开（公告）日：2013-11-20