(1R,12R)-5,8,14-triazatetracyclo[10.3.1.02,11.04,9]hexadeca-2,4,6,8,10-pentaene

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯氮卓类
• 英文名称: (1R,12R)-5,8,14-triazatetracyclo[10.3.1.02,11.04,9]hexadeca-2,4,6,8,10-pentaene
• 化学式: C₁₃H₁₃N₃
• 分子量: 211.26
• InChiKey: JQSHBVHOMNKWFT-IUCAKERBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  16
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  37.8
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

代谢

伐尼克兰经历最少的代谢，92%以原形从尿液中排出。

Varenicline undergoes minimal metabolism, with 92% excreted unchanged in the urine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

伐尼克兰在体内经历极少量代谢，92%以原形通过尿液排出，不到10%以代谢物形式排出。尿液中的次要代谢物包括伐尼克兰N-羧甲酰葡萄糖苷酸和羟基伐尼克兰。在循环系统中，伐尼克兰占药物相关物质的91%。循环中的次要代谢物包括伐尼克兰N-羧甲酰葡萄糖苷酸和N-葡萄糖基伐尼克兰。

Varenicline undergoes minimal metabolism with 92% excreted unchanged in the urine and less than 10% excreted as metabolites. Minor metabolites in urine include varenicline N-carbamoylglucuronide and hydroxyvarenicline. In circulation, varenicline comprises 91% of drug related material. Minor circulating metabolites include varenicline N-carbamoylglucuronide and N-glucosylvarenicline.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

伐尼克兰在治疗期间并未与血清酶水平升高率大于安慰剂治疗的情况相关联，但关于这些异常的信息有限，偶尔会有无症状的ALT升高导致停药的报告。在数千名患者的上市前关键注册试验中，伐尼克兰并未与黄疸或肝炎的病例相关。自获得许可以来，有罕见的病例报告在开始使用伐尼克兰后的4周内出现无黄疸的血清酶升高，但主要发生在有其他肝脏损伤原因的患者中（酒精性肝病、丙型肝炎）。这种损伤在过程中是自限性的，并未与免疫过敏或自身免疫特征相关。在冰岛，已经报告了一例伐尼克兰肝毒性的病例（案例1），自该药物引入以来，估计有20,000人接受了该药物治疗。

Varenicline has not been associated with rates of serum enzyme elevations during therapy greater than occurs with placebo therapy, but information on these abnormalities is limited and occasional instances of asymptomatic ALT elevations leading to drug discontinuation have been reported. In prelicensure pivotal registration trials in several thousand patients, varenicline was not associated with cases of jaundice or hepatitis. Since licensure, rare case reports of serum enzyme elevations without jaundice arising within 4 weeks of starting varenicline have been published, but largely in patients with other causes of liver injury (alcoholic liver disease, hepatitis C). The injury was self-limited in course and not associated with immunoallergic or autoimmune features. In Iceland, a single case of varenicline hepatotoxicity has been reported (Case 1), there having been an estimated 20,000 persons treated with the drug in the country since its introduction.

来源:LiverTox

毒理性

• 相互作用

药物与细胞色素P-450（CYP）同工酶代谢的药物或影响CYP同工酶的药物之间不太可能发生药代动力学相互作用。体外研究显示，瓦伦尼克林在体外不抑制CYP同工酶1A2、2A6、2B6、2C8、2C9、2C19、2D6、2E1或3A4/5。该药物也不诱导CYP同工酶1A2或3A4。

Pharmacokinetic interactions unlikely with drugs metabolized by or affecting cytochrome P-450 (CYP) isoenzymes. In vitro studies indicate that varenicline does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4/5 in vitro. The drug also does not induce CYP isoenzymes 1A2 or 3A4.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

戒烟（有或无伐尼克兰）导致的生理变化可能会改变某些药物（例如，茶碱、华法林、胰岛素）的药代动力学或药效学；可能需要调整剂量。制造商表示，在接受伐尼克兰与其他药物的患者中，临床经验并未发现临床重要相互作用的证据。

Physiologic changes resulting from smoking cessation (with or without varenicline) may alter the pharmacokinetics or pharmacodynamics of some drugs (e.g., theophylline, warfarin, insulin); dosage adjustment may be required. The manufacturer states that clinical experience in patients receiving varenicline with other drugs has not revealed evidence of clinically important interactions.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

药物动力学相互作用不太可能。与接受经皮尼古丁和安慰剂的人群相比，联合治疗（伐尼克兰和经皮尼古丁替代疗法）的不良反应（恶心、头痛、呕吐、头晕、消化不良、疲劳）发生率增加，并且停药率也增加。伐尼克兰与其他戒烟疗法联合使用时的安全性和有效性尚未进行研究。

Pharmacokinetic interaction unlikely. Increased incidence of adverse effects (nausea, headache, vomiting, dizziness, dyspepsia, fatigue) and increased rate of discontinuance of combination (varenicline and transdermal nicotine replacement) therapy compared with those receiving transdermal nicotine and placebo. Safety and efficacy of varenicline in combination with other smoking cessation therapies have not been studied.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

药物动力学相互作用不太可能。戒烟可能会影响华法林的药物动力学。

Pharmacokinetic interaction unlikely. Warfarin pharmacokinetics may be affected by smoking cessation.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

伐尼克兰口服给药后，通常在3-4小时内达到最大血浆浓度。在多次口服伐尼克兰后，稳态条件在4天内达到。在推荐剂量范围内，伐尼克兰在单次或重复剂量后表现出线性药代动力学。在一项质量平衡研究中，伐尼克兰口服给药后的吸收几乎完全，系统可用性约为90%。伐尼克兰的口服生物利用度不受食物或每日定时给药的影响。伐尼克兰的血浆蛋白结合率较低（<=20%）且与年龄和肾功能无关。

Maximum plasma concentrations of varenicline occur typically within 3-4 hours after oral administration. Following administration of multiple oral doses of varenicline, steady-state conditions were reached within 4 days. Over the recommended dosing range, varenicline exhibits linear pharmacokinetics after single or repeated doses. In a mass balance study, absorption of varenicline was virtually complete after oral administration and systemic availability was ~90%. Oral bioavailability of varenicline is unaffected by food or time-of-day dosing. Plasma protein binding of varenicline is low (</=20%) and independent of both age and renal function.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Varenicline 主要以原药形式通过尿液排出。药物的肾排泄主要是通过肾小球滤过和积极的肾小管分泌。

Varenicline is eliminated principally in urine as unchanged drug. Renal elimination of the drug occurs primarily through glomerular filtration along with active tubular secretion.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Varenicline 在动物中会分布到乳汁中。尚不清楚 Varenicline 是否会分布到人乳中。

Varenicline is distributed into milk in animals. Not known whether varenicline is distributed into human milk.

来源:Hazardous Substances Data Bank (HSDB)