[(7S,11S,12R,13S,14R,15R,16R,17S,18S)-2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-26-[(4-methylpiperazin-1-yl)iminomethyl]-6,23-dioxo-8,30-dioxa-24-azatetracyclo[23.3.1.14,7.05,28]triaconta-1(29),2,4,9,19,21,25,27-octaen-13-yl] acetate | 13292-46-1

• 物质功能分类: 原料药 - 抗生素类药物 - 利福霉素类药
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: [(7S,11S,12R,13S,14R,15R,16R,17S,18S)-2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-26-[(4-methylpiperazin-1-yl)iminomethyl]-6,23-dioxo-8,30-dioxa-24-azatetracyclo[23.3.1.14,7.05,28]triaconta-1(29),2,4,9,19,21,25,27-octaen-13-yl] acetate
• CAS: 13292-46-1
• 化学式: C₄₃H₅₈N₄O₁₂
• 分子量: 822.9
• InChiKey: JQXXHWHPUNPDRT-GHGVGPBWSA-N

物化性质

• 熔点：
  183°C (dec.)
• 沸点：
  761.02°C (rough estimate)
• 密度：
  1.1782 (rough estimate)
• 溶解度：
  在氯仿的溶解度为50mg/mL，澄清
• 颜色/状态：
  Red to orange platelets from acetone
• 气味：
  ODORLESS
• 蒸汽压力：
  3.1X10-34 mm Hg at 25 °C /Estimated/
• 亨利常数：
  Henry's Law constant = 2.7X10-42 atm-cu m/mol at 25 °C /Estimated/
• 稳定性/保质期：
  Very stable in dimethyl sulfoxide; rather stable in water.
• 解离常数：
  Zwitterion with pKa 1.7 related to the 4-hydroxy and pKa 7.9 related to the 3-piperazine nitrogen

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  59
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  220
• 氢给体数：
  6
• 氢受体数：
  15

ADMET

代谢

利福平和苯巴比妥对异烟肼和肼在大鼠体内的代谢命运的影响进行了研究。雄性Wistar大鼠在空腹后，以30 mg/kg的剂量腹腔注射利福平6天，或者以50 mg/kg的剂量注射苯巴比妥3天作为预处理。预处理后，大鼠以40 mg/kg的剂量腹腔注射异烟肼。收集24小时尿液样本，并通过气相色谱/质谱法测定尿液中肼和乙酰肼的浓度。大鼠被处死，肝脏立即在原位灌洗并匀浆，确定肝脏中代谢物的分布。另外，在大鼠颈静脉注射5 mg/kg肼后0.5、1、2、3和4小时分别采集血液样本，并测定血浆中肼的浓度。在注射异烟肼后1小时内，在大鼠的肝脏和血浆中检测到了肼和乙酰肼。利福平或苯巴比妥预处理组的肼浓度显著低于对照组；乙酰肼的浓度没有改变。利福平或苯巴比妥预处理显著增加了肼通过尿液排出的量。

The effects of rifampicin ... and phenobarbital ... on the metabolic fate of isoniazid ... and hydrazine ... were studied in rats. Male Wistar rats were fasted and injected with rifampicin at 30 mg/kg ip for 6 days, or with phenobarbital at 50 mg/kg for 3 days as pretreatment. After pretreatment, the rats were injected with isoniazid at 40 mg/kg ip. Twenty four hour urine samples were collected, and urinary concentrations of hydrazine and acetylhydrazine ... were determined by gas chromatography/mass spectrometry. The rats were /sacrificed/, livers were immediately perfused in situ and homogenized, and hepatic distribution of metabolites was determined. Separately, blood was sampled and plasma hydrazine concn were determined at 0.5, 1, 2, 3, and 4 hr after a jugular injection of 5 mg/kg hydrazine. Within 1 hr after injection of isoniazid, hydrazine and acetylhydrazine were detected in the liver and plasma. The concn of hydrazine in rifampicin or phenobarbital pretreated groups were significantly lower than those in the control group; the concn of acetylhydrazine were not altered. Pretreatment with rifampicin or phenobarbital resulted in a marked incr in the urinary elimination of hydrazine. ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

在豚鼠、兔子和人类中，尿液中利福平的主要代谢物是25-O-去乙酰利福平；在狗和老鼠的体液中检测到了一种未识别的代谢物。

In guinea pigs, rabbits and humans, major metabolite of rifampicin in urine and bile is 25-o-deacetyl rifampicin; in body fluids of dogs and rats an unidentified metabolite has been detected.

来源:Hazardous Substances Data Bank (HSDB)

代谢

利福平在肝脏中被代谢成为一种去乙酰化衍生物，这种衍生物也具有抗菌活性。

Rifampin is metabolized in the liver to a deacetylated derivative which also possesses antibacterial activity.

来源:Hazardous Substances Data Bank (HSDB)

代谢

几株快速生长的分枝杆菌被发现能够使利福平失效。这些生物体产生的两种失活化合物（RIP-Ma和RIP-Mb）与之前报道的抗生素衍生物不同，即磷酸化或葡萄糖化的衍生物。RIP-Ma和RIP-Mb的结构被确定为3-甲酰-23-[O-(alpha-D-核糖呋喃糖基)]利福霉素SV和23-[O-(alpha-D-核糖呋喃糖基)]利福平，分别为。据我们所知，这是已知的第一个作为抗生素失活机制的核糖基化例子。

Several fast growing Mycobacterium strains were found to inactivate rifampin. Two inactivated compounds (RIP-Ma and RIP-Mb) produced by these organisms were different from previously reported derivatives, i.e., phosphorylated or glucosylated derivatives, of the antibiotic. The structures of RIP-Ma and RIP-Mb were determined to be those of 3-formyl-23-[O-(alpha-D-ribofuranosyl)]rifamycin SV and 23-[O-(alpha-D-ribofuranosyl)]rifampin, respectively. To our knowledge, this is the first known example of ribosylation as mechanism of antibiotic inactivation.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

鉴定：利福平是一种用于治疗结核病的抗生素。利福平是由利福霉素抗生素的半合成衍生物，由地中海链霉菌的一种菌株发酵产生。发酵产生利福霉素B。利福霉素B通过一系列合成反应转变而成。颜色：红色至橙色无臭粉末。它微溶于水、丙酮、四氯化碳、酒精和乙醚。它易溶于氯仿、二甲基亚砜（DMSO）；溶于乙酸乙酯、甲醇和四氢呋喃。在酸性pH下，其在水溶液中的溶解度增加。熔点138至188°C。由于利福平是两性离子，它有2个pKa，pKa 1.7与4-羟基相关，pKa 7.9与3-哌嗪氮相关。1%的水悬浮液pH值为4.5至6.5。适应症：利福平的主要适应症是治疗结核病（肺内和肺外病变）和麻风病。它也用于消除携带者的脑膜炎奈瑟菌（但不推荐用于活动性脑膜炎球菌感染）和革兰阳性（金黄色葡萄球菌和表皮葡萄球菌、链球菌、绿色链球菌和肺炎链球菌）及革兰阴性细菌（流感嗜血杆菌B型）。它对某些衣原体有抗性，在体外对某些病毒（痘病毒和腺病毒）在高剂量下有活性。最近它也被用于治疗布鲁氏菌病。人类暴露：主要风险和靶器官：主要靶器官是肝脏和胃肠道系统。关注的风险包括有毒肝炎，胆汁和胆红素浓度升高，贫血，白细胞减少，血小板减少和出血。临床效果总结：过量的临床表现在一定程度上是不良反应的扩展。在治疗期间，利福平通常耐受性良好，然而，间歇性使用利福平时常见不良反应。这些包括发热反应、嗜酸性粒细胞增多、白细胞减少、血小板减少、紫癜、溶血和休克、肝毒性和肾毒性。胃肠道不良反应可能很严重，导致伪膜性结肠炎。神经毒性效应包括混乱、共济失调、视力模糊、眩晕和周围神经炎。常见毒性效应是红色皮肤和体液橙色素沉着。已有因不良反应致死的报道。利福平对人类胎儿没有显著影响。它扩散到乳汁和其他体液中。禁忌症：已知对利福平过敏的病例禁用。它可能在怀孕期间禁忌（因为在大鼠研究中观察到致畸性，且药物对胎儿的影响尚未确定），除非存在严重结核病等疾病。在严重肝功能损害和黄疸的酗酒者中禁用。进入途径：口服：这是常见的进入途径。眼部：用于治疗眼部衣原体感染。静脉注射：利福平可以静脉给药。动力学：暴露途径的吸收：利福平容易从胃肠道吸收（90%）。口服剂量后1.5至4小时达到血浆峰浓度。食物可能会减少并延迟吸收。暴露途径的分布：静脉注射利福平的分布与口服途径相同。循环中的89%的利福平与血浆蛋白结合。它是脂溶性的。它广泛分布在身体组织和体液中。当脑膜发炎时，利福平进入脑脊液。它达到肺部、支气管分泌物、胸膜液、其他腔隙液体、肝脏、胆汁和尿液的治疗水平。利福平有很高的胎盘转移，胎儿与母体血清水平比为0.3。它分布到乳汁中。表观分布体积（VD）为0.93至1.6 L/kg。暴露途径的生物半衰期：生物半衰期为3小时（2至5小时）。单次高剂量或肝病患者中，半衰期增加。在前两周治疗期间，半衰期减少了40%，因为增强了胆汁排泄和诱导了自身的代谢。重复给药后，血浆半衰期可能缩短。治疗开始时利福平的半衰期从3.5小时降至1至2周每日给药后的2小时，此后保持恒定。在贫血存在下，血浆半衰期缩短至1.8至3.1小时。代谢：大约85%的利福平由肝脏微粒体酶代谢为其主要和活性代谢物——脱乙酰利福平。利福平经历肠肝循环，但脱乙酰形式不会。利福平增加了自己的代谢速率。利福平也可能在其他身体部位失活。甲酰利福平是尿液中的代谢物，在尿液中自发形成。暴露途径的消除：利福平代谢物脱乙酰利福平通过胆汁和尿液排出。大约50%的利福平剂量在24小时内消除，6至30%的药物以原形从尿液中排出，而15%以活性代谢物形式排出。大约43至60%的口服剂量在粪便中排出。固有全身清除率为3.5（

IDENTIFICATION: Rifampicin is an antibiotic used to treat tuberculosis. Rifampicin is a semisynthetic derivative of rifamycin antibiotics which are produced by the fermentation of a strain of Streptomyces mediterranei. The fermentation produces rifamycin B. Rifamycin B is transformed by a series of synthesis reactions. Color: Red to orange odorless powder. It is very slightly soluble in water, acetone, carbon tetrachloride, alcohol and ether. It is freely soluble in chloroform, DMSO; soluble in ethyl acetate and methyl alcohol and tetrahydrofuran. Solubility in aqueous solutions is increased at acidic pH. Melting point 138 to 188 °C. Rifampicin has 2 pKa since it is a Zwitterion, pKa 1.7 related to 4-hydroxy and pKa 7.9 related to 3-piperazine nitrogen. A 1% suspension in water has pH 4.5 to 6.5. Indications: The primary indications for rifampicin are for treatment of tuberculosis (pulmonary and extrapulmonary lesions) and for leprosy. It is also useful for elimination of Neisseria meningococci in carriers (but not recommended for active meningococcal infection) and for Gram positive (Staphylococcus aureus and epidermidis, Streptococcus pyogenes, viridans and pneumoniae) and gram negative bacteria (Hemophilus influenzae type B). It has some anti-chlamydial activity and in vitro activity against some viruses (poxvirus and adenovirus) at high doses. It has recently been used for brucellosis. HUMAN EXPOSURE: Main risks and target organs: The main target organs are the liver and the gastrointestinal system. Risks of concern are toxic hepatitis with elevation of bile and bilirubin concentrations, anaemia, leukopenia, thrombocytopenia and bleeding. Summary of clinical effects: Some clinical manifestations of overdosage are extension of adverse effects. During therapy, rifampicin is usually well tolerated, however, adverse side-effects are common in intermittent rifampicin intake. These include febrile reaction, eosinophilia, leukopenia, thrombocytopenia, purpura, hemolysis and shock, hepatotoxicity and nephrotoxicity. Gastrointestinal adverse reactions may be severe leading to pseudomembranous colitis. Neurotoxic effects include confusion, ataxia, blurring of vision, dizziness and peripheral neuritis. A common toxic effect is red skin with orange discoloration of body fluids. Fatalities from adverse reactions have been reported. Rifampicin has shown no significant effects on the human fetus. It diffuses into milk and other body fluids. Contraindications: Rifampicin is contraindicated in known cases of hypersensitivity to the drug. It may be contraindicated in pregnancy (because of teratogenicity noted in animal studies and since the effects of drugs on fetus has not been established) except in the presence of a disease such as severe tuberculosis. It is contraindicated in alcoholics with severely impaired liver function and with jaundice. Routes of entry: Oral: This is the common route of entry. Eye: Use for ocular chlamydial infection treatment. Parenteral: Rifampicin may be given intravenously. Kinetics: Absorption by route of exposure: Rifampicin is readily absorbed from the gastrointestinal tract (90%). Peak plasma concentration occurs at 1.5 to 4 hours after an oral dose. Food may reduce and delay absorption. Distribution by route of exposure: Intravenous rifampicin has the same distribution as in oral route. Eighty nine percent of rifampicin in circulation is bound to plasma proteins. It is lipid soluble. It is widely distributed in body tissues and fluids. When the meninges are inflamed, rifampicin enters the cerebrospinal fluid. It reaches therapeutic levels in the lungs, bronchial secretions, pleural fluid, other cavity fluids, liver, bile, and urine. Rifampicin has a high degree of placental transfer with a fetal to maternal serum level ratio of 0.3. It is distributed into breast milk. The apparent volume of distribution (VD) is 0.93 to 1.6 L/kg. Biological half-life by route of exposure: The biological half-life is three hours range (2 to 5 hours). This half-life increases with single high doses or with liver disease. The half-life decreases by 40% during the first two weeks of therapy because of enhanced biliary excretion and induction of its own metabolism. Plasma half-life may decrease after repeated administration. The half-life of rifampicin decreased from 3.5 hours at start of therapy to 2 hours after daily administration for 1 to 2 weeks, and remained constant thereafter. Plasma half-life shortens to 1.8 to 3.1 hours in the presence of anemia. Metabolism: Approximately 85% of rifampicin is metabolised by the liver microsomal enzymes to its main and active metabolite-deacetylrifampicin. Rifampicin undergoes enterohepatic recirculation but not the deacetylated form. Rifampicin increases its own rate of metabolism. Rifampicin may also be inactivated in other parts of the body. Formylrifampicin is a urinary metabolite that spontaneously forms in the urine. Elimination by route of exposure: Rifampicin metabolite deacetylrifampicin is excreted in the bile and also in the urine. Approximately 50% of the rifampicin dose is eliminated within 24 hours and 6 to 30% of the drug is excreted unchanged in the urine, while 15% is excreted as active metabolite. Approximately 43 to 60% of oral dose is excreted in the feces. Intrinsic total body clearance is 3.5 (+/- 1.6) mL/min/kg, reduced in kidney failure. Renal clearance is 8.7 mL/min/kg. Rifampicin levels in the plasma are not significantly affected by haemodialysis or peritoneal dialysis. Rifampicin is excreted in breastmilk (1 to 3 ug/ml). Mode of action: Toxicodynamics: Rifampicin causes cholestasis at both the sinusoids and canaliculi of the liver because of defect in uptake by hepatocytes and defect in excretion, respectively. Rifampicin may produce liver dysfunction. Hepatitis occurs in 1% or less of patients, and usually in the patient with pre-existing liver disease. Hypersensitivity reactions may occur, usually characterized by a "flu" type syndrome. Nephrotoxicity appears to be related to a hypersensitivity reaction and usually occurs after intermittent or interrupted therapy. It has been suggested that some of the adverse effects associated with rifampicin may be attributed to its metabolite desacetylrifampicin. It is lipid soluble, and thus can reach and kill intracellular, as well as extracellular, Mycobacteria. Rifampicin does not bind to mammalian nuclear RNA polymerase and therefore does not affect the RNA synthesis in human beings. Rifampicin, however, may affect mammalian mitochondrial RNA synthesis at a concentration that is 100 times higher than that which affects bacterial RNA synthesis. Pharmacodynamics: Rifampicin has high activity against mycobacterial organisms, including Mycobacterium tuberculosis and M.leprae. It is also active against Staphylococcus aureus, coagulase negative staphylocci, Listeria monocytogenes, Neisseria meningitidis, Haemophilus influenzae, Legionella spp., Brucella, some strains of Escherichia coli, Proteus mirabilis, anaerobic cocci, Clostridium spp., and Bacteroides. Rifampicin is also reported to exhibit an immunosuppressive effect which has been seen in some animal experiments, but this may not be clinically significant in humans. Rifampicin may be bacteriostatic or bactericidal depending on the concentration of drug attained at site of infection. The bactericidal actions are secondary to interfering with the synthesis of nucleic acids by inhibiting bacterial DNA-dependent RNA polymers at the B-subunit thus preventing initiation of RNA transcription, but not chain elongation. Carcinogenicity: One report showed that nasopharyngeal lymphoma may develop after therapy of two years for Pott's disease. This was probably secondary to the immunosuppressive effects of rifampicin. An increase of hepatomas in female mice has been reported in one strain of mice,following one year's administration of rifampicin at a dosage of 2 to 10% of the maximum human dosage. Because of only limited evidence available for the carcinogenicity of rifampicin in mice and the absence of epidemiological studies, no evaluation of the carcinogenicity of rifampicin to humans could be made. Teratogenicity: Malformation and death have been reported in infants born to mothers exposed to rifampicin, although it was the same frequency as in the general population. Interactions: Food lowers peak blood levels because of interference with absorption of rifampicin. Antacids containing aluminium hydroxide reduced the bioavailability of rifampicin. Para-amino salicylic acid granules may delay rifampicin absorption (because of bentonite present as a granule excipient) which leads to an inadequate serum level of rifampicin. These two drugs should be given 8 to 12 hours apart. Isoniazid and rifampicin interaction has led to hepatotoxicity. (Note: slow acetylators of isoniazid have accelerated rifampicin clearance). Alcohol intake with rifampicin increases the risk for hepatotoxicity. Rifampicin induces microsomal enzymes of the liver and therefore accelerates metabolism of some drugs, beta blockers, calciferol, coumadins, cyclosporin, dapsone, diazepam, digitalis, hexobarbital, ketoconazole, methadone, oral contraceptive pills, oral hypoglycaemic agents, phenytoin, sulphasalazine, theophylline, some anti-arrhythmic drugs such as disopyramide, lorcainide, mexiletine, quinidine, and verapamil. Rifampicin induces liver steroid metabolizing enzyme thus lowering the levels of glucocorticoids and mineralocorticoids. Rifampicin lowers chloramphenicol serum levels when the two drugs are used together. When rifampicin and oral contraceptives are used concomitantly, there is decreased effectiveness of oral contraceptives because of the rapid destruction of oestrogen by rifampicin and the latter being a potent inducer of hepatic metabolising enzymes. It was reported that rifampicin may be the cause of some menstrual disorders when used with oral contraceptive pills. When rifampicin and corticosteroids are used, there is a reduction of plasma cortisol half-life and increased urinary excretion of cortisol metabolite. It may be necessary to double or quadruple the dosage of the steroid. When rifampicin and cyclosporin are taken, the serum levels of cycloserine may be lowered. In the therapy of leprosy, rifampicin may induce dapsone metabolism, however, this is of minor significance in the clinical setting. The clinical condition of patients, who are on rifampicin and also taking digoxin for heart failure, may deteriorate because of falling digoxin levels. Hence there may be a need to increase the dosage of digitalis. Another cardiac drug is disopyramide which is used for cardiac dysrhythmias, and when taken with rifampicin, there is a decrease in levels of the antiarrhythmic agent. The clinical importance of this effect has yet to be determined. Patients on methadone maintenance for narcotic detoxification may develop narcotic withdrawal when methadone plasma levels decreased as a consequence of taking rifampicin at the same time. It is also possible that rifampicin alters the distribution of methadone. Rifampicin induces hepatic enzyme metabolism which can decrease metoprolol blood levels, although this may be clinically insignificant. In patients who receive rifampicin and phenytoin together, there is an increase of clearance of phenytoin by twofold, significantly reducing the effects of the anticonvulsant drug. Modification of quinidine dose is necessary when this is used with rifampicin because of the risk of ventricular dysrhythmias. It is recommended that quinidine dosage be always readjusted when one adds or discontinues rifampicin therapy. When verapamil and rifampicin are taken together, rifampicin induces liver enzymes which increases the metabolism of the calcium channel blocker leading to undetectable verapamil levels. Rifampicin can lower the plasma calciferol (Vitamin D) level because of induction of enzyme activity. Barbiturates and salicylates decrease the activity of rifampicin. Effects with clofazimine range from no effect to decrease in the rate of absorption of rifampicin, delay in the time it reaches peak plasma concentrations, decrease in plasma rifampicin concentrations. Rifampicin can decrease the therapeutic levels of ketoconazole when given together. When rifampicin is taken with oral hypoglycemic agents (tolbutamide and chlorpropamide), these latter medications had a decrease in elimination half-lives. Rifampicin enhances antifungal actions of amphotericin B. Probenecid intake diminishes hepatic uptake of rifampicin. ANIMAL/PLANT STUDIES: Carcinogenicity: An increase of hepatomas in female mice has been reported in one strain of mice, following one year's administration of rifampicin at a dosage of 2 to 10% of the maximum human dosage. Teratogenicity: Teratogenic effects noted in rodents treated with high doses 100 to 150 mg/kg bodyweight daily in rodents have been reported to cause cleft palate and spina bifida. Rifampicin is teratogenic for rats and mice. Mutagenicity: The available studies on mutagenicity indicate an absence of mutagenic effect.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

利福平引起的肝损伤虽然不常见，但已有详细记录。长期使用利福平治疗与10%至20%的患者出现轻微、短暂的血清转氨酶水平升高有关，这些异常通常不需要调整剂量或停药。利福平对血清胆红素水平有不同寻常和似是而非的影响。在大多数患者中，血清胆红素水平（包括总胆红素和间接胆红素）在利福平治疗的前几天会增加，然后通常会降至基线以下。此外，利福平治疗还可能与开始治疗后的几周内直接和总胆红素显著增加有关，而无需肝损伤的证据。这种效应在患有显著基础肝病的患者中可见，如肝硬化，以及在罕见Dubin Johnson综合征或肝细胞管蛋白（称为ABC C2或MRP2）突变的患者中可见，该蛋白负责将结合胆红素从肝细胞转运到胆小管。 利福平还与罕见但明显的临床肝损伤病例有关，伴有症状和黄疸，这可能是严重的，甚至致命的。由于利福平通常与异烟肼和/或吡嗪酰胺联合使用，后两者也是已知的肝毒性药物，因此患者在使用利福平时发生的急性肝损伤可能难以归因于单一药物，并且有证据表明这些联合用药比单独药物更可能导致损伤。通常，利福平引起的损伤发生在1到6周内（这有助于将其与通常较晚出现的异烟肼损伤区分开来），但已有报告称有更长时间潜伏期的病例。在损伤初期，血清酶模式通常是肝细胞型的，但与异烟肼相比，可能是胆汁淤积性和混合性的。如发热、皮疹、关节痛、面部水肿和嗜酸性粒细胞增多等肝外表现以及自身抗体的形成是不常见的。 可能性评分：A（已确立的明显临床肝损伤原因）。

Liver injury from rifampin is uncommon, but well documented. Long term therapy with rifampin is associated with minor, transient elevations in serum aminotransferase levels in 10% to 20% of patients, abnormalities that usually do not require dose adjustment or discontinuation. Rifampin has unusual and paradoxical effects on serum bilirubin levels. In most patients, serum bilirubin levels (both total and indirect) increase during the first few days of rifampin therapy, whereupon they usually decrease to below baseline. In addition, rifampin therapy can be associated with a prominent increase in both direct and total bilirubin within a few weeks of starting therapy without evidence of liver injury. This effect is seen in patients with significant underlying liver disease such as cirrhosis, as well as in the rare individual with Dubin Johnson syndrome or mutations in the hepatic canicular protein known as ABC C2 or MRP2 which is responsible for transport of conjugated bilirubin from the hepatocyte into the bile canalicus. Rifampin is also associated with rare instances of clinically apparent liver injury accompanied by symptoms and jaundice, which can be severe and even fatal. Because rifampin is usually given in combination with isoniazid and/or pyrazinamide, two other known hepatotoxic agents, the cause of the acute liver injury in patients on rifampin may be difficult to relate to a single agent and some evidence suggests that these combinations are more likely to cause injury than the individual drugs would suggest. Typically, the onset of injury due to rifampin is within 1 to 6 weeks (which may help separate it from isoniazid injury which is often later), but cases with longer latency have been reported. The serum enzyme pattern is usually hepatocellular at the onset of injury, but can cholestatic and mixed in contrast to isoniazid. Extrahepatic manifestations such as fever, rash, arthralgias, facial edema and eosinophilia are uncommon as is autoantibody formation. Likelihood score: A (well established cause of clinically apparent liver injury).

来源:LiverTox

毒理性

• 致癌性证据

没有关于人类的数据。动物致癌性的证据有限。总体评估：第3组：该物质对人类致癌性无法分类。

No data are available in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌物分类

国际癌症研究机构致癌剂：利福平

IARC Carcinogenic Agent:Rifampicin

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构（IARC）致癌物分类：第3组：对其对人类的致癌性无法分类

IARC Carcinogenic Classes:Group 3: Not classifiable as to its carcinogenicity to humans

来源:International Agency for Research on Cancer (IARC)

吸收、分配和排泄

利福平在全身分布，并存在于许多器官和体液中，包括脑脊液（CSF）。这一点从药物可能导致尿液、粪便、唾液、痰、泪液和汗液呈现橙红色这一事实中可以得到最好的体现……。

Rifampin is distributed throughout the body and is present in effective concentrations in many organs and body fluids, including the CSF. This is perhaps best exemplified by the fact that the drug may impart an orange-red color to the urine, feces, saliva, sputum, tears, and sweat ... .

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

药物剂量的多达30%通过尿液排出，60%到65%通过粪便排出；其中不到一半可能是未改变的抗生素。

Up to 30% of a dose of the drug is excreted in the urine and 60% to 65% in the feces; less than half of this may be unaltered antibiotic.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

利福平口服给药后，血浆中的峰值浓度在2到4小时内达到；摄入600毫克后，该值约为7微克/毫升，但个体间存在较大差异。

The oral administration of rifampin produces peak concentrations in plasma in 2 to 4 hours; after ingestion of 600 mg this value is about 7 ug/mL, but there is considerable variability

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

rifampin在胆汁中被迅速排泄，并随后发生肠肝循环。

Following absorption from the gastrointestinal tract, rifampin is eliminated rapidly in the bile, and an enterohepatic circulation ensues.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn
• 安全说明：
  S26,S36
• 危险类别码：
  R22,R36/37/38
• WGK Germany：
  1,3
• 海关编码：
  2941903000
• RTECS号：
  VJ7000000
• 危险标志：
  GHS07
• 危险性描述：
  H302
• 危险性防范说明：
  P301 + P312 + P330

制备方法与用途

理化性质

利福平（又译：利发霉素、甲哌利福霉素、甲哌力复霉素、威福仙、仙道伦、力复平或利米定，INN：Rifampicin）是一种广谱抗生素药物，属于利福霉素家族。它对结核杆菌有较强的抗菌作用，并且对于革兰氏阳性或阴性细菌、病毒等也有疗效。

理化性质方面，利福平为红色或暗红色的结晶状粉末，不溶于水。通常以胶囊或片剂的形式口服使用。与其它抗结核药物联合应用能增强药效并延缓耐药菌株的产生。

化学性质

利福平呈现橙红色的片状结晶或砖红色的粉末状固体，在183-188℃条件下会分解。它易溶于氯仿和二甲基亚砜，也能溶解在乙酸乙酯、甲醇和四氢呋喃中。溶于水（pH＜6）、丙醇及四氯化碳中。干燥粉末可在常温下稳定5年以上，但其水溶液在室温条件下10小时后会失效；然而，在加入还原剂（如抗坏血酸）之后可以减少分解，并且在二甲亚砜中极为稳定。

用途

利福平是一种广谱抗生素，对结核分枝杆菌、革兰氏阳性菌和部分革兰氏阴性菌具有抑菌或杀菌作用。主要用于治疗耐药结核分枝杆菌感染以及耐药金葡菌感染，并且对麻风病有一定的疗效。

生产方法

利福平是通过将利福霉素SV氧化成利福霉素S，再与甲醛和叔丁胺进行甲酰化反应生成3-甲酰基叔丁胺利福霉素S。然后，该物质在维生素C的作用下还原，并与1-甲基-4-氨基哌嗪缩合而得。

其他用途

利福平可用作医药中间体。具有广谱抗菌作用，对革兰氏阳性球菌及结核杆菌表现出良好的抗菌活性，其抗菌谱与利福平相同。作为原料药时，主要用于生产抗结核抗生素。它能够抑制DNA的重组和蛋白质插入成熟的病毒颗粒，并通过结合RNA聚合酶的β-亚单元来抑制RNA合成的起始过程。

总之，利福平是一种重要的广谱抗生素药物，具有强大的抗菌作用，并且在多种疾病的治疗中显示出显著的效果。

文献信息

• Integrase inhibitors
  申请人：Cai R. Zhenhong

  公开号：US20080058315A1

  公开（公告）日：2008-03-06

  Tricyclic compounds, protected intermediates thereof, and methods for inhibition of HIV-integrase are disclosed.

  三环化合物，其受保护的中间体，以及用于抑制HIV整合酶的方法被披露。
• [EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
  申请人：MERCK SHARP & DOHME

  公开号：WO2016089721A1

  公开（公告）日：2016-06-09

  The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

  本发明涉及甲基噁唑化合物，其为促进睡眠的受体拮抗剂。本发明还涉及所述化合物在潜在治疗或预防涉及促进睡眠的神经和精神疾病和疾病中的用途。本发明还涉及包含这些化合物的组合物。本发明还涉及这些组合物在潜在预防或治疗涉及促进睡眠的疾病中的用途。
• [EN] OXAZOLIDINONE COMPOUNDS AND METHODS OF USE THEREOF AS ANTIBACTERIAL AGENTS<br/>[FR] COMPOSÉS OXAZOLIDINONE ET PROCÉDÉS D'UTILISATION DE CES DERNIERS EN TANT QU'AGENTS ANTIBACTÉRIENS
  申请人：MERCK SHARP & DOHME

  公开号：WO2017066964A1

  公开（公告）日：2017-04-27

  The present invention relates to oxazolidinone compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, E, and R1 are as defined herein. The present invention also relates to compositions which comprise at least one oxazolidinone compound of the invention. The invention also provides methods for inhibiting growth of mycobacterial cells as well as a method of treating mycobacterial infections by Mycobacterium tuberculosiscomprising administering a therapeutically effective amount of an oxazolidinone of the invention and/or apharmaceutically acceptable salt thereof, or a composition comprising such compound and/or salt.

  本发明涉及式(I)的噁唑烷酮化合物及其药学上可接受的盐，其中A、E和R1如本文所定义。本发明还涉及包含本发明至少一种噁唑烷酮化合物的组合物。该发明还提供了抑制分枝杆菌细胞生长的方法，以及通过给予治疗有效量的本发明的噁唑烷酮和/或其药学上可接受的盐，或包含该化合物和/或盐的组合物来治疗结核分枝杆菌感染的方法。
• [EN] DERIVATIVES OF AMANITA TOXINS AND THEIR CONJUGATION TO A CELL BINDING MOLECULE<br/>[FR] DÉRIVÉS DE TOXINES D'AMANITES ET LEUR CONJUGAISON À UNE MOLÉCULE DE LIAISON CELLULAIRE
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2017046658A1

  公开（公告）日：2017-03-23

  Derivatives of Amernita toxins of Formula (I), wherein, formula (a) R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X, L, m, n and Q are defined herein. The preparation of the derivatives. The therapeutic use of the derivatives in the targeted treatment of cancers, autoimmune disorders, and infectious diseases.

  Amernita毒素的衍生物的化学式（I），其中，化学式（a）中的R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、X、L、m、n和Q在此处被定义。这些衍生物的制备。这些衍生物在靶向治疗癌症、自身免疫性疾病和传染病中的治疗用途。
• [EN] A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS<br/>[FR] CONJUGUÉ D'UN AGENT CYTOTOXIQUE À UNE MOLÉCULE DE LIAISON CELLULAIRE AVEC DES LIEURS RAMIFIÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020257998A1

  公开（公告）日：2020-12-30

  Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.

  提供了一种将细胞毒性药物与一个侧链连接分子结合的共轭物。它提供了制备细胞毒性分子与细胞结合配体的共轭物的侧链连接方法，以及在靶向治疗癌症、感染和免疫性疾病中使用该共轭物的方法。