Tiotropium

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 英文名称: Tiotropium
• 英文别名: [(1S,2S,4R,5R)-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonan-7-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate
• 化学式: C19H22NO4S2+
• 分子量: 392.5
• InChiKey: LERNTVKEWCAPOY-FPISHFTHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  116
• 氢给体数：
  1
• 氢受体数：
  6

ADMET

代谢

替索罗姆在体内不被大量代谢。74%的静脉注射剂量以未改变的药物形式通过尿液排出。替索罗姆非酶解地裂解为不活跃的代谢物N-甲基莨菪碱和二噻吩基乙酸。体外实验显示细胞色素P-450依赖性氧化和谷胱甘肽结合形成更进一步的代谢物。

Tiotropium is not heavily metabolized in the body. 74% of an intravenous dose is excreted in the urine as unchanged drug. Tiotropium is nonenzymatically cleaved to the inactive metabolites N-methylscopine and dithienylglycolic acid. _In vitro_ experiments show cytochrome P-450 dependent oxidation and glutathione conjugation to further metabolites.

来源:DrugBank

毒理性

• 肝毒性

与其他抗胆碱能药物一样，噻托溴铵并未与肝酶升高或临床上明显的肝脏损伤发生联系。其安全性较高的一个主要原因是通过吸入器给药时其系统性吸收较低。 关于抗胆碱能药物的安全性和潜在肝毒性的参考资料，在抗胆碱能药物概述部分之后给出。 药物类别：抗胆碱能药物

Like other anticholinergic agents, tiotropium has not been linked to episodes of liver enzyme elevations or clinically apparent liver injury. A major reason for its safety may relate to its low systemic absorption when administered by inhaler. References on the safety and potential hepatotoxicity of anticholinergics are given together after the Overview section on the Anticholinergic Agents. Drug Class: Anticholinergic Agents

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：尽管没有关于使用噻托溴铵的已发表数据，但其使用产生的母体血清水平微不足道，且任何药物进入母乳中都不会被婴儿吸收。母亲吸入噻托溴铵对哺乳婴儿的风险很小。 ◉ 对哺乳婴儿的影响：截至修订日期，未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，未找到相关的已发表信息。

◉ Summary of Use during Lactation:Although no published data exist on the use of tiotropium, its use produces negligible maternal serum levels and any drug in breastmilk would not be absorbed by the infant. The risk to the breastfed infant of maternal tiotropium inhalation is small. ◉ 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

• 蛋白质结合

替洛罗喷在血浆中与蛋白质的结合率为72%。

Tiotropium is 72% protein bound in plasma.

来源:DrugBank

吸收、分配和排泄

• 吸收

吸入溶液的33%会到达系统循环，而口服溶液的生物利用度为2-3%。吸入用干粉的生物利用度为19.5%。吸入用噻托溴铵定量喷雾剂在5-7分钟内达到最大浓度。

33% of an inhaled solution reaches systemic circulation, while oral solutions have a bioavailability of 2-3%. A dry powder for inhalation is 19.5% bioavailable. Tiotropium metered spray for inhalation reaches a maximum concentration in 5-7 minutes.

来源:DrugBank

吸收、分配和排泄

• 排除途径

静脉注射的噻托溴铵有74%未经改变地通过尿液排出。干粉吸入剂量的14%未经改变地通过尿液排出。慢性阻塞性肺病（COPD）患者在每日吸入5微克连续21天后的24小时尿液中排出率为18.6%，而哮喘患者的排出率为12.8%。

74% of intravenous tiotropium was excreted unchanged in urine. 14% of a dry powder inhalation dose was excreted unchanged in the urine. 24 hour urinary excretion after 21 days of 5µg once daily inhalation in patients with COPD is 18.6% and in patients with asthma is 12.8%.

来源:DrugBank

吸收、分配和排泄

• 分布容积

替洛罗平的分布体积为32L/kg。

The volume of distribution of tiotropium is 32L/kg.

来源:DrugBank

吸收、分配和排泄

• 清除

在健康受试者中，噻托溴铵的总体清除率为880毫升/分钟，这些人每天接受5微克的剂量。噻托溴铵的肾清除率为669毫升/分钟。65岁以下的患者的清除率为365毫升/分钟，而65岁及以上的患者的清除率为271毫升/分钟。这种清除率的降低与AUC（药时曲线下面积）或Cmax（最大血药浓度）的增加无关。

The total clearance of tiotropium is 880mL/min in healthy subjects receiving 5µg daily. The renal clearance of tiotropium was 669mL/min. Patients <65 years old demonstrated a clearance of 365mL/min while patients ≥65 demonstrated a clearance of 271mL/min. This decreased clearance is not associated with increased AUC or C_max.

来源:DrugBank