雷尼替丁 | 66357-35-5

• 物质功能分类: 原料药 - 消化系统用药 - 抑制胃酸分泌药
• 分子结构分类: 有机化合物 - 有机氮化合物
• 中文名称: 雷尼替丁
• 中文别名: 胃安太定；盐酸雷尼替丁；N"-甲基-N-[2-[[[5-[(二甲氨基)甲基]-2-呋喃基]-甲基]硫代]乙基]-2-硝基-1,1-乙烯二胺盐酸盐
• 英文名称: ranitidine
• 英文别名: N-[2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine；N-{2-[5-(dimethylaminomethyl)furfurylthio]ethyl}-N'-methyl-2-nitro-1,1-ethenediamine；ranitidine 50；Rantidine；Ranital；Ulcuran；1-N'-[2-[[5-[(dimethylamino)methyl]furan-2-yl]methylsulfanyl]ethyl]-1-N-methyl-2-nitroethene-1,1-diamine
• CAS: 66357-35-5
• 化学式: C₁₃H₂₂N₄O₃S
• 分子量: 314.409
• InChiKey: VMXUWOKSQNHOCA-UHFFFAOYSA-N

物化性质

• 熔点：
  69-70°C
• 沸点：
  437.1±45.0 °C(Predicted)
• 密度：
  1.184±0.06 g/cm3(Predicted)
• 溶解度：
  在水中的溶解度1.8 mg/mL
• Caco2细胞的药物渗透性：
  0.49

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  21
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  112
• 氢给体数：
  2
• 氢受体数：
  7

ADMET

代谢

尿液中的主要代谢物是N-氧化物，它占剂量的不到4%。ranitidine的其他代谢物包括S-氧化物（1%）和去甲基ranitidine（1%）。粪便中含有剩余的ranitidine剂量。肝脏功能不全会导致ranitidine药代动力学参数发生小但临床上不重要的变化。

The major metabolite in the urine is N-oxide, which represents less than 4% of the dose. Other metabolites of ranitidine include S-oxide (1%) and desmethyl ranitidine (1%). The feces contain the remainder of the excreted ranitidine dose. Liver dysfunction has been shown to cause small, but clinically insignificant, changes in various ranitidine pharmacokinetic parameters.

来源:DrugBank

代谢

雷尼替丁在口服给药后经历显著的首过代谢。它在肝脏中被代谢为药理学上不活跃的去甲基雷尼替丁、雷尼替丁-N-氧化物和雷尼替丁-S-氧化物。

Ranitidine undergoes significant first-pass metabolism after oral admin. It is metabolized in the liver to the pharmacologically inactive desmethylranitidine, ranitidine-N-oxide, and ranitidine-S-oxide.

来源:Hazardous Substances Data Bank (HSDB)

代谢

静脉注射剂量中的10%以下以代谢物的形式排出；静脉注射剂量的68%至79%和口服剂量的30%以未改变的药物形式出现在尿液中。

Less than 10% of an iv or oral dose is excreted as metabolites; 68% to 79% of an iv dose and 30% of an oral dose appear in the urine as unchanged drug.

来源:Hazardous Substances Data Bank (HSDB)

代谢

疑似N-氧化物代谢物相对于母体氨基酸化合物的色谱行为被描述，目的是预测N-氧化物的保留数据。模型化合物通过反相高效液相色谱和标准薄层色谱系统进行评估，并生成数据以预测雷尼替丁N-氧化物和他莫昔芬N-氧化物基于母体化合物的保留值。实际值和预测值之间的偏差大于预期。

The chromatographic behavior of putative N-oxide metabolites relative to the parent amino compounds with the aim of predicting retention data for N-oxides is described. Model compounds were evaluated by reversed phase HPLC and standard TLC systems and the data generated to predict retention values for ranitidine N-oxide and tamoxifen N-oxide based upon those of the parent compounds. The deviation between actual and predicted values was larger than expected.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

长期使用雷尼替丁治疗与1%至4%的患者血清转氨酶水平小幅升高有关，但在安慰剂接受者中也有类似的报告率。ALT（肝酶）升高通常是无症状的和短暂的，可能在不需要调整剂量的情况下解决。在接受雷尼替丁治疗的患者中报告了罕见的明显临床肝损伤病例，但发病时间和损伤模式有很大差异（案例1-3）。发病时间可能短至几天，长至几个月，但通常在6周内。血清酶升高的模式从肝细胞型到胆汁淤积型不等，大多数病例为“混合”肝细胞-胆汁淤积型。损伤很少严重，通常在停药后迅速解决，通常在4到12周内。肝脏活检组织学常显示明显的中央静脉周围坏死。免疫过敏特征（皮疹、发热、嗜酸性粒细胞增多）可能出现（案例2），但不太常见，自身抗体形成也不常见。

Chronic therapy with ranitidine has been associated with minor elevations in serum aminotransferase levels in 1% to 4% of patients, but similar rates were reported in placebo recipients. The ALT elevations are usually asymptomatic and transient and may resolve without dose modification. Rare instances of clinically apparent liver injury have been reported in patients receiving ranitidine, but the time to onset and pattern of injury has varied greatly (Cases 1-3). Onset can be as short as a few days to as long as several months, but is usually within 6 weeks. The pattern of serum enzyme elevation varies from hepatocellular to cholestatic, most cases being “mixed” hepatocellular-cholestatic. The injury is rarely severe and usually resolves rapidly upon stopping, generally within 4 to 12 weeks. Liver biopsy histology often shows prominent centrolobular necrosis. Immunoallergic features (rash, fever, eosinophilia) can occur (Case 2) but are uncommon, as is autoantibody formation.

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：尽管患者之间存在个体差异，但雷尼替丁在母乳中的剂量低于在新生儿中使用的剂量。然而，发现雷尼替丁会自发分解成一种致癌化学物质，导致其在美国和其他国家被撤出市场。建议使用其他药物。 ◉ 对哺乳婴儿的影响：一名54天大的哺乳期婴儿在母亲每12小时服用150毫克雷尼替丁2天后，没有观察到不良反应。 ◉ 对泌乳和母乳的影响：已知组胺H2受体阻断剂可刺激催乳素分泌。一些研究发现，静脉注射超过100毫克的雷尼替丁或长期口服使用会增加血清催乳素水平，并报告了罕见的男性乳房发育病例。对于已经建立泌乳的母亲，催乳素水平可能不会影响她的哺乳能力。

◉ Summary of Use during Lactation:Although interpatient variability exists, the dose of ranitidine in breastmilk is less than the dose used in newborn infants. However, the finding that ranitidine spontaneously breaks down to a cancer-causing chemical caused its removal from the market in the US and other countries. Other drugs are recommended. ◉ Effects in Breastfed Infants:One 54-day-old breastfed infant had no observable adverse effects after maternal ingestion of ranitidine 150 mg every 12 hours for 2 days. ◉ Effects on Lactation and Breastmilk:Histamine H2-receptor blockade is known to stimulate prolactin secretion. Ranitidine in intravenous doses over 100 mg or during long-term oral use have increased serum prolactin in some studies, and rare cases of gynecomastia have been reported. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 副作用

皮肤致敏剂 - 一种可以诱导皮肤产生过敏反应的制剂。

Skin Sensitizer - An agent that can induce an allergic reaction in the skin.

来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases

毒理性

• 相互作用

在一项志愿者参与的随机交叉研究中，通过口服15毫克咪达唑仑后，无论是否在服用前未使用任何药物，还是在服用雷尼替丁24小时治疗后，血浆中咪达唑仑水平在24小时内被测定。雷尼替丁的给药显著增加了苯二氮䓬类药物的生物利用度，并导致在服用咪达唑仑后的前6小时内血浆水平更高。

In a randomized crossover study in volunteers plasma midazolam levels were est for 24 hr following 15 mg by mouth, either preceded by no medication or following 24 hr therapy with ranitidine. Admin of ranitidine significantly incr bioavailability of the benzodiazepine and resulted in higher plasma levels for the first 6 hr after taking midazolam.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

十名健康男性受试者静脉注射安替比林（1.2克）、地西泮（10毫克）或劳拉西泮（2毫克），在两次随机分配的场合下进行，一次在未服药状态下，一次在同时服用每12小时150毫克的治疗剂量雷尼替丁的情况下。雷尼替丁对人类肝脏药物氧化（通过安替比林和地西泮的清除率测量）或人类药物结合（通过劳拉西泮的清除率测量）均无影响。

Ten healthy male subjects were injected iv with antipyrine (1.2 g), diazepam (10 mg) or lorazepam (2 mg) on 2 randomly assigned occasions, once in the drug-free state & once while concurrently taking a therapeutic ranitidine dose of 150 mg every 12 hr. Ranitidine has no effect on either human hepatic drug oxidation, as measured by antipyrine and diazepam clearance, or human drug conjugation, as measured by lorazepam clearance.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

雷尼替丁吸收迅速，给药后1-3小时内达到峰值浓度，患者间差异很大。由于肝脏代谢，生物利用度约为50%-60%。在一项健康男性的药代动力学研究中，AUC 0-无限大约为2,488.6 ng x h/mL，中位Tmax为2.83小时。食物或抗酸药对吸收的影响有限。一项临床研究发现，在禁食状态下给予强效抗酸药（150 mmol）的受试者，雷尼替丁的吸收减少。

Ranitidine is rapidly absorbed with peak concentrations reached within 1-3 hours after administration, and varying greatly among patients. Bioavailability is about 50%-60% due to hepatic metabolism. In a pharmacokinetic study of healthy males, the AUC 0-infinity was about 2,488.6 ng x h/mL and the median Tmax was 2.83 hours. Food or antacids have limited effects on absorption. One clinical study found that the administration of a potent antacid (150 mmol) in subjects in the fasted state led to decreased absorption of ranitidine.

来源:DrugBank

吸收、分配和排泄

• 消除途径

这种药物主要在尿液中排泄，但也会在粪便中排泄。约30%的单次口服剂量在摄入后24小时内以未改变的药物形式在尿液中测量到。

This drug is mainly excreted in the urine but also excreted in the feces. About 30% of a single oral dose has been measured in the urine as unchanged drug within 24 hours of ingestion.

来源:DrugBank

吸收、分配和排泄

• 分布容积

分布容积高于体液，大约为1.4 L/kg。它集中在乳汁中，但不易进入脑脊液。

The volume of distribution is higher than body volume, and measures at approximately 1.4 L/kg. It concentrates in breast milk, but does not readily distribute into the cerebrospinal fluid.

来源:DrugBank

吸收、分配和排泄

• 清除

根据FDA的处方信息，肾清除率约为410毫升/分钟。另一个资源提到血浆清除率大约为600毫升/分钟。老年人和那些肝肾功能受损者的清除率会降低。建议在肾功能受损的患者中将雷尼替丁的剂量减少一半。

Renal clearance is about 410 mL/min according to FDA prescribing information. Another resource mentions a plasma clearance of approximately 600 ml/min. Clearance is decreased in the elderly and those with impaired or hepatic renal function. It is recommended to decrease the dose of ranitidine by one-half in patients with renal impairment.

来源:DrugBank

吸收、分配和排泄

十二名正常男性受试者在开始连续输注胃泌素（2微克/千克/小时）前90分钟口服了20、40或80毫克的雷尼替丁。雷尼替丁使氢离子输出量分别减少了29%、50%和70%，分泌体积分别减少了21%、37%和47%。同样剂量的雷尼替丁使胃蛋白酶活性分别减少了8%、50%和49%。血清中雷尼替丁峰浓度与氢离子输出量（r=0.81，P<0.001）和体积（r=0.71，P<0.01）的百分比减少在2小时内呈正相关。氢离子输出量减少50%与165微克/升的雷尼替丁血清峰浓度相关，受试者在口服给药后60至120分钟达到血清峰浓度。

Twelve normal male subjects received 20, 40, or 80 mg of ranitidine orally 90 min before starting a 3-hr continuous infusion of pentagastrin, 2 ug/kg/hr. Ranitidine reduced hydrogen ion output by 29%, 50% and 70% & secretion volume by 21%, 37%, and 47%. Pepsin activity was reduced by 8%, 50% & 49% by the same doses. Peak serum concn was correlated positively with percent reduction in hydrogen ion output (r= 0.81, P= less than 0.001) & volume (r= 0.71, P less than 0.01) over a 2-hr period. A 50% inhibition of hydrogen ion output was associated with a peak ranitidine serum concn of 165 ug/l and subjects reached peak serum concn 60 to 120 min after oral dosing.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S22,S24/25
• WGK Germany：
  2
• 海关编码：
  2932999099
• RTECS号：
  KM6557000
• 储存条件：
  Desiccate at +4°C

制备方法与用途

药理作用

盐酸雷尼替丁是抗酸药及抗溃疡病药物雷尼替丁的盐酸盐形式。其药理作用与雷尼替丁相同。雷尼替丁又称为呋喃硝胺，化学结构类似于西咪替丁，在西咪替丁的基础上合成了一种新型H2受体拮抗剂。相比西咪替丁，它具有较少的不良反应，并且抑制胃酸分泌的作用是西咪替丁的5～8倍。

盐酸雷尼替丁对胃、十二指肠溃疡疗效显著，兼具速效和长效特点，能有效抑制组胺及五肽胃泌素刺激引起的胃酸分泌。其抑制夜间胃酸分泌量与24小时胃酸量按质量比和摩尔浓度比计算的效价分别为西咪替丁的4～9倍和5～12倍。

在抑制胃酸分泌的同时，它也能抑制胃蛋白酶分泌，而不影响胃泌素及性激素等物质的分泌。尽管盐酸雷尼替丁能与细胞色素P450结合，但其亲和力仅为西咪替丁的1/10。口服或胃内给药可以抑制消化性、应激性和吲哚美辛引起的动物胃溃疡以及组胺引起的豚鼠胃十二指肠溃疡，其抑制作用与药物浓度成正比。

药代动力学

盐酸雷尼替丁胶囊口服吸收迅速但不完全，有轻微的首过效应。主要在肝脏代谢，通过肾脏排泄。成人服用一粒（每天两次），8岁以下儿童、孕妇及哺乳期妇女禁用。连续用药不宜超过7天，如症状未缓解应及时就医咨询。

化学性质

盐酸雷尼替丁是一种白色或淡黄色结晶性粉末，有轻微的异臭和微苦涩的味道，极易吸湿。它易溶于甲醇或水，稍溶于乙醇而不溶于氯仿或丙酮。熔点为69-70℃。

用途

盐酸雷尼替丁是一种强效、长效的组胺H2受体拮抗剂，能有效地抑制基础胃酸及胃泌素刺激引起的胃酸分泌，降低胃酸和胃酶活性，作用比西咪替丁强5～8倍且维持时间长。它适用于良性胃十二指肠溃疡、术后溃疡、反流性食道炎及卓-艾氏综合症等。

生产方法

盐酸雷尼替丁的生产涉及以下步骤：首先将N-甲基-1-甲硫基-2-硝基乙烯甲胺（230克）溶于400毫升水中，加热至45～50℃搅拌，4小时内滴加321克2-[[5-[(二甲氨基)甲基]呋喃-2-基]甲基]硫代乙胺。继续搅拌3.5小时后再回流0.5小时，冷却至70℃后，加入2升4-甲基-2-戊酮，在减压下共沸蒸出水分，然后在50℃和10克活性炭作用后过滤除去活性炭。

将滤液冷至10℃，析出雷尼替丁结晶，经过干燥处理最终得到约380克产品，熔点为69～70℃。

反应信息

• 作为反应物：
  描述：

  雷尼替丁 在 盐酸 作用下， 以 乙酸乙酯 、 异丙醇 为溶剂， 反应 0.75h， 以91.7%的产率得到ranitidine hydrochloride
  参考文献：
  名称：

  ANHYDROUS TABLET OF RANITIDINE HYDROCHLORIDE WITH DOUBLE-LAYER COATING AND ITS COMPOSITION

  摘要：

  公开号：

  EP1171102B1
• 作为产物：
  描述：

  5-氯甲基呋喃-2-甲醛 在 sodium hydride 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 4.08h， 生成 雷尼替丁
  参考文献：
  名称：

  合成 雷尼替丁 （赞塔克）来自纤维素 5-（氯甲基）糠醛

  摘要：

  生物质衍生的平台化学品 5-（氯甲基）糠醛 转变为重磅炸弹抗溃疡药 药品 雷尼替丁 （赞塔克）分四个步骤进行，总体孤立收率达到68％。

  DOI：

  10.1039/c1gc15537g
• 作为试剂：
  描述：

  蔗糖 在 yeast sucrase (3.2.1.26) 、 雷尼替丁 作用下， 生成 果糖 、 葡萄糖
  参考文献：
  名称：

  Ranitidine induces inhibition and structural changes in sucrase

  摘要：

  Ranitidine is an antagonist of histamine-2 (H-2) receptor. It is employed to treat peptic ulcer and other conditions in which gastric acidity must be reduced. Sucrase is a hydrolytic enzyme that catalyzes the breakdown of sucrose to its monomer content. A liquid of yeast sucrase was developed for treatment of congenital sucrase-isomaltase deficiency (CSID) in human. In this study, the effect of ranitidine on yeast sucrase activity was investigated. Our results showed that ranitidine binds to sucrase and inhibits the enzyme in a noncompetitive manner. The K-i and IC50 values were measured to be about 2.3 and 2.2 mM, respectively. Fluorescence measurement showed conformational changes after binding of ranitidine to the enzyme. The fluorescence spectra showed that ranitidine could bind to both free enzyme and enzyme-substrate complex, which was accompanied with reduction of emission intensity and red shift production.

  DOI：

  10.3109/14756366.2011.601414

文献信息

• Synergistic Effects of ppm Levels of Palladium on Natural Clinochlore for Reduction of Nitroarenes
  作者：Mohammad Gholinejad、Erfan Oftadeh、Mohammad Shojafar、José M. Sansano、Bruce H. Lipshutz

  DOI：10.1002/cssc.201901535

  日期：2019.9.20

  occurring clay clinochlore with ppm amounts of palladium leads to a new and very effective reagent for the reduction of numerous aromatic nitro species. When palladium nanoparticles are supported on pyridyltriazole-modified clinochlore, iron within clinochlore acts synergistically with palladium to catalyze the reduction of a wide variety of nitroarenes at room temperature in aqueous media. Based on

  用ppm量的钯增强改性的天然存在的粘土斜绿石，会导致一种新型的，非常有效的还原大量芳香硝基物种的试剂。当钯纳米颗粒负载在吡啶基三唑改性的氯丁酸上时，氯丁二酸中的铁与钯协同作用，在室温下在水性介质中催化多种硝基芳烃的还原。根据电子因子的计算，发现该催化剂体系符合绿色化学标准，可以循环使用多达五次。
• [EN] PROCESS FOR PRODUCTION OF ALKANESULFONIC ACID<br/>[FR] PROCEDE POUR LA PRODUCTION D'UN ACIDE ALCANE SULFONIQUE
  申请人：COUNCIL SCIENT IND RES

  公开号：WO2004058693A1

  公开（公告）日：2004-07-15

  The present invention relates to a process for the production of alkanesulfonic acid. More particularly, the present invention relates to a process for the production of alkanesulfonic acid from alkyl mercaptan effluents generated in chemical industries. The process of the invention comprises the oxidation of the entire alkyl mercaptan generated as an effluent in the chemical industries to serve two concomitant purposes: (1) complete removal of obnoxious odour, and (2) value addition by the production of alkanesulfonic acids selectively in quantitative yields.

  本发明涉及一种制备烷基磺酸的方法。更具体地说，本发明涉及一种从化学工业中产生的烷基硫醇废水中制备烷基磺酸的方法。该发明的方法包括将整个在化学工业中产生的烷基硫醇废水氧化，以实现两个同时的目的：(1)完全去除难闻的气味，(2)通过选择性地生产烷基磺酸实现增值，且可以获得定量收率。
• 高稳定性枸缘酸铋雷尼替丁的合成新方法
  申请人：江苏汉斯通药业有限公司

  公开号：CN107501216B

  公开（公告）日：2021-01-19

  本发明公开了一种高稳定性枸缘酸铋雷尼替丁的合成新方法，包括如下步骤：（1）制备原料溶液；（2）反应制备雷尼替丁；（3）雷尼替丁纯化；（4）成盐反应；（5）脱色除菌；（6）制备枸缘酸铋雷尼替丁成品。本发明一种高稳定性枸缘酸铋雷尼替丁的合成新方法，通过合理的工艺设计，提高了雷尼替丁的质量和稳定性，从而提高了枸缘酸铋雷尼替丁的药理性能和稳定性；本发明的合成方法，原料成本低，合成工艺条件温和，可控性高，产品收率高，适合工业化生产。
• 雷尼替丁口服制剂治疗糜烂性食管炎的新适 应症
  申请人：上海金城素智药业有限公司

  公开号：CN108727312B

  公开（公告）日：2021-05-18

  本发明公开了一种雷尼替丁及其制备方法，以及一种雷尼替丁制剂、复方制剂及其制备方法。其中，雷尼替丁的杂质含量低，稳定性高，且制备方法简单；由其制备的雷尼替丁制剂和复方制剂的生物利用度和安全性较高。本发明提供的雷尼替丁、雷尼替丁制剂及复方制剂，能够有效治疗和维持治疗糜烂性食管炎。
• Process for production of alkanesulfonic acid
  申请人：COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH

  公开号：US20040186316A1

  公开（公告）日：2004-09-23

  The present invention relates to a process for the production of alkanesulfonic acid. More particularly, the present invention relates to a process for the production of alkanesulfonic acid from alkyl mercaptan effluents generated in chemical industries. The process of the invention comprises the oxidation of the entire alkyl mercaptan generated as an effluent in the chemical industries to serve two concomitant purposes: (1) complete removal of obnoxious odour, and (2) value addition by the production of alkanesulfonic acids selectively in quantitative yields.

  本发明涉及一种制备烷磺酸的方法。更具体地说，本发明涉及一种从化工行业产生的烷基巯基废水中制备烷磺酸的方法。本发明的方法包括将在化工行业作为废水产生的整个烷基巯基氧化，以实现两个同时的目的：（1）完全去除刺鼻气味，以及（2）通过有选择性地定量产生烷磺酸实现价值增加。