[2,15,17,32-Tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-1'-(2-methylpropyl)-6,23-dioxospiro[8,33-dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1(32),2,4,9,19,21,24,26,30-nonaene-28,4'-piperidine]-13-yl] acetate

• 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: [2,15,17,32-Tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-1'-(2-methylpropyl)-6,23-dioxospiro[8,33-dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1(32),2,4,9,19,21,24,26,30-nonaene-28,4'-piperidine]-13-yl] acetate
• 英文别名: [2,15,17,32-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-1'-(2-methylpropyl)-6,23-dioxospiro[8,33-dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1(32),2,4,9,19,21,24,26,30-nonaene-28,4'-piperidine]-13-yl] acetate
• 化学式: C₄₆H₆₂N₄O₁₁
• 分子量: 847.0
• InChiKey: ZWBTYMGEBZUQTK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  61
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  209
• 氢给体数：
  5
• 氢受体数：
  14

ADMET

代谢

...像利福平一样，利福布汀在多次给药期间会诱导其自身的代谢。利福布汀被广泛代谢。利福布汀的两个主要代谢物有助于其抗菌活性。利福布汀能诱导肝脏代谢，但不如利福平的诱导作用强。...

... Like rifampin rifabutin induces its own metabolism during multiple dosing. Rifabutin is extensively metabolized. The two major metabolites of rifabutin contribute to its antimicrobial activity. Rifabutin induces hepatic metabolism but is not as potent an inducer as is rifampin. ...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

由于其使用范围有限，利福布汀对肝脏的影响不如利福平明确，但它们可能是相似的。因此，在HIV感染患者中使用利福布汀预防MAC的研究中，3%至8%的患者出现了轻微、短暂的血清转氨酶水平升高，但这些异常很少需要调整剂量或停药。临床上明显的利福布汀引起的肝损伤尚未有报道，但它可能和利福平在导致急性肝损伤的潜力上相似。由于利福布汀通常与其他治疗HIV感染的药物联合使用，因此很难将使用利福布汀方案的患者的急性肝损伤归因于单一药物。通常，利福平引起的损伤发生在1到6周内，损伤开始时血清酶模式通常是肝细胞型的，但可能与异烟肼和吡嗪酰胺不同，可以是胆汁淤积性和混合性的。由于利福平肝毒性引起的肝外表现，如发热、皮疹、关节痛、水肿和嗜酸性粒细胞增多是不常见的，自体抗体形成也是如此。利福布汀的这种肝毒性潜力尚未得到特别证明，一些归因于利福平的明显肝毒性的患者在没有复发的肝损伤的情况下耐受利福布汀。

Because of its limited use, the effects of rifabutin on the liver have been less well defined than those of rifampin, but they are likely to be similar. Thus, studies on the prevention of MAC in HIV infected patients with rifabutin, minor, transient elevations in serum aminotransferase levels occurred in 3% to 8% of patients, but these abnormalities rarely required dose adjustment or discontinuation. Clinically apparent liver injury due to rifabutin has not been reported, but it is likely to be similar to rifampin in its potential for causing acute liver injury. Because rifabutin is usually given in combination with other agents used to treat HIV infection, the cause of the acute liver injury in patients on rifabutin-containing regimens may be difficult to relate to a single agent. Typically, the onset of injury due to rifampin is within 1 to 6 weeks and the serum enzyme pattern is usually hepatocellular at the onset of injury, but can cholestatic and mixed in contrast to isoniazid and pyrazinamide. Extrahepatic manifestations due to rifampin hepatotoxicity such as fever, rash, arthralgias, edema and eosinophilia are uncommon as is autoantibody formation. This potential for hepatotoxicity has not been demonstrated specifically for rifabutin, and some patients with apparent hepatotoxicity attributed to rifampin have tolerated rifabutin without recurrence of liver injury.

来源:LiverTox

毒理性

• 相互作用

利福平与利福布汀在结构上相关；利福平已知能降低许多药物的活动性，包括氨茶碱；香豆素或茚满二酮衍生物抗凝剂；口服降糖药；巴比妥类；系统性β-肾上腺素能阻断剂；氯霉素；氯贝丁酯；含口服雌激素的避孕药；糖皮质激素和盐皮质激素类固醇；环孢素；氨苯砜；地西泮；洋地黄糖苷；双异丙吡胺；雌莫司汀；雌激素；酮康唑；美西律；三己酚；苯妥英；喹尼丁；茶碱；托卡尼丁；口服维拉帕米，这是因为利福平是肝脏细胞色素P450系统的肝酶诱导剂。利福布汀本身的药物相互作用数据不可用；因此，建议在同时使用这些药物的利福布汀患者应受到监测，因为可能存在的药物相互作用的显著性尚不清楚。

Rifampin is structurally related to rifabutin; rifampin is known to reduce the activity of many drugs /including aminophylline; coumarin- or indandione-derivative anticoagulants; oral antidiabetic agents; barbiturates; systemic beta-adrenergic blocking agents; chloramphenicol; clofibrate; oral estrogen-containing contraceptive; glucocorticoid and mineralocorticoid corticosteriods; cyclosporine; dapsone; diazepam; digitalis glycoside; disopyramide; estramustine; estrogens; ketoconazole; mexiletine; oxtriphylline; phenytoin; qiunidine; theophylline; tocainide; oral verapamil/ due to its hepatic enzyme inducer of the hepatic cytochrome p450 system that rifampin. Drug interaction data are unavailable for rifabutin itself; therefore, it is recommended that patients taking rifabutin concurrently with these medications be monitored since the significance of possible drug interactions is not known.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

使用氟康唑和利福布汀进行的药代动力学研究表明，氟康唑似乎会增加利福布汀的血清浓度；然而，这被认为没有临床意义，利福布汀的剂量在接收氟康唑的患者中不需要调整；此外，氟康唑的药代动力学没有改变。

Pharmacokinetic studies with fluconazole and rifabutin show that fluconazole appears to increase the serum concentration of rifabutin; however, this is not thought to have clinical significance and rifabutin dosing does not need to be modified in patients receiving fluconazole; in addition, the pharmacokinetics of fluconazole were unchanged.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

与利福布汀联合用药对美沙酮的药代动力学没有显著影响；然而，如果出现症状或戒毒反应，少数患者可能需要调整美沙酮的剂量。

Concurrent administration with rifabutin has no significant effect on the pharmacokinetics of methadone; however, a few patients may require methadone dosage modifications if symptoms or narcotic withdrawal occur.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

稳态血浆浓度和血浆浓度-时间曲线下的面积（AUC）在健康志愿者和HIV阳性患者的I期临床试验中，重复使用利福布汀后有所下降；峰浓度和AUC的平均降低分别为48%和32%。然而，对两个III期临床试验中齐多夫定的浓度-时间数据进行群体药代动力学分析显示，利福布汀对齐多夫定的表观清除率有非显著的增加趋势。体外研究已经证实，利福布汀不影响齐多夫定对HIV的抑制作用。

Steady-state plasma concentrations and the area under the plasma concentration-time curve (AUC) of zidovudine were decreased after repeated rifabutin dosing in healthy volunteers and HIV-positive patients in phase I trials; the mean deceases in peak plasma concentration and AUC were 48% and 32%, respectively. However, a population pharmacokinetic analysis of zidovudine concentration versus time data from two phase III studies showed a nonsignificant trend for rifabutin to increase the apparent clearance of zidovudine. In vitro studies have demonstrated that rifabutin does not affect the inhibition of HIV by zidovudine.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

容易从胃肠道吸收。高脂肪餐减慢了吸收速率，但并不影响吸收的程度。生物利用度大约为20%。

Readily absorbed from gastrointestinal tract. High-fat meals slow the rate, but not the extent, of absorption. Bioavailability is approximately 20%.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

高度亲脂性；广泛分布，大量摄取于细胞内组织。利福布汀能穿过血脑屏障；脑脊液中的浓度大约是对应血清浓度的50%。

Highly lipophilic; widely distributed with extensive intracellular tissue uptake. Rifabutin crosses the blood-brain barrier; cerebrospinal fluid concentrations are approximately 50% of the corresponding serum concentration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

消除：30% 经粪便；5% 未改变在尿液中；5% 未改变在胆汁中；53% 以代谢物形式在尿液中。透析 - 血液透析预计不会增强消除。

Elimination: 30% fecal; 5% unchanged in the urine; 5% unchanged in the bile; 53% in urine as metabolites. In dialysis - Hemodialysis is not expected to enhance elimination.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

因为利福布丁是一种亲脂性药物，其在组织中的浓度比血浆中的浓度高出很多（5到10倍）。

Because rifabutin is a lipophilic drug, concentrations are substantially higher (5- to 10-fold) in tissue than in plasma.

来源:Hazardous Substances Data Bank (HSDB)