Pharmakon1600-01500529 | 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: Pharmakon1600-01500529
• 英文别名: [(7S,9E,11S,12R,13R,14R,15R,16R,17S,19E,21Z)-2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-26-[(E)-(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-BUTCOYSSSA-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大鼠在空腹状态下，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，立即在原位灌洗肝脏并匀浆，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，在大鼠肝脏和血浆中检测到肼和乙酰肼。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：红色至橙色无味粉末。它微溶于水、丙酮、四氯化碳、酒精和乙醚。它易溶于氯仿、DMSO；溶于乙酸乙酯、甲醇和四氢呋喃。在水溶液中的溶解度在酸性pH下增加。 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（肺内外病变）和麻风病。它也用于消除脑膜炎奈瑟菌携带者（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A群、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）。它对某些病毒（痘病毒和腺病毒）在高剂量下具有抗衣原体活性和体外活性。最近它也被用于布鲁氏菌病。 人体暴露：主要风险和靶器官：主要靶器官是肝脏和胃肠系统。关注的风险包括毒性肝炎，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。常见毒性效应是皮肤发红和体液橙黄色变色。已有因不良反应致死的报告。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。在怀孕期间可能禁忌使用（因为动物研究中观察到的致畸性，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：用于治疗眼衣原体感染。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。它广泛分布于身体组织和体液中。当脑膜发炎时，利福平进入脑脊液。它达到肺、支气管分泌物、胸膜液、其他腔隙液、肝、胆汁和尿液的治疗水平。利福平具有高度胎盘转移，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。治疗前两周，半衰期因增强胆汁排泄和诱导自身代谢而减少40%。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，但脱乙酰形式不循环。利福平增加自身的代谢速率。利福平也可能在其他身体部位失活。甲酰胺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泄。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。内在总清除率为3.5（+/- 1.6）mL/min/kg，在肾

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