[(7S,9Z,11S,12R,13S,14R,15R,16R,17S,18S,19Z,21Z)-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,9Z,11S,12R,13S,14R,15R,16R,17S,18S,19Z,21Z)-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-BQVAUQFYSA-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联胺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，持续6天，或者以50 mg/kg的剂量腹腔注射苯巴比妥，持续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/质谱法测定尿液中联胺和乙酰联胺的浓度。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联胺后0.5、1、2、3和4小时分别采血，并测定血浆中联胺的浓度。在异烟肼注射后1小时内，在大鼠的肝脏和血浆中检测到了联胺和乙酰联胺。利福平或苯巴比妥预处理组的联胺浓度显著低于对照组；乙酰联胺的浓度没有改变。利福平或苯巴比妥预处理导致大鼠尿液中联胺的排泄显著增加。

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效化合物（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效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（肺结核和肺外结核病变）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，链球菌属，绿色链球菌和肺炎链球菌）和革兰阴性细菌（流感嗜血杆菌B型）。它对某些病毒（痘病毒和腺病毒）在体外高剂量时具有一定的抗衣原体活性和活性。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延伸。在治疗期间，利福平通常耐受性良好，然而，间歇性服用利福平时不良反应很常见。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。常见的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。它可能在怀孕期间是禁忌的（因为在大鼠研究中观察到致畸性，且药物对胎儿的�