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Rifabutin (also known as Ansamycin) is a semisynthetic ansamycin and broad-spectrum antibiotic with potent antimycobacterial properties. Rifabutin is being used as prophylaxis against disseminated Mycobacterium avium complex infection in HIV-positive patients.
Physicochemical Properties
| Molecular Formula | C46H62N4O11 |
| Molecular Weight | 847.0047 |
| Exact Mass | 846.441 |
| Elemental Analysis | C, 65.23; H, 7.38; N, 6.61; O, 20.78 |
| CAS # | 72559-06-9 |
| Related CAS # | Rifabutin-d7;2747918-39-2 |
| PubChem CID | 136276712 |
| Appearance | Purple to purplish red solid powder |
| Density | 1.3±0.1 g/cm3 |
| Boiling Point | 969.6±65.0 °C at 760 mmHg |
| Melting Point | 169-171ºC |
| Flash Point | 540.2±34.3 °C |
| Vapour Pressure | 0.0±0.3 mmHg at 25°C |
| Index of Refraction | 1.623 |
| LogP | 3.45 |
| Hydrogen Bond Donor Count | 5 |
| Hydrogen Bond Acceptor Count | 14 |
| Rotatable Bond Count | 5 |
| Heavy Atom Count | 61 |
| Complexity | 1880 |
| Defined Atom Stereocenter Count | 9 |
| SMILES | C12=C3C(=C(C)C4O[C@](C)(OC=C[C@H](OC)[C@@H](C)[C@@H](OC(=O)C)[C@H](C)[C@@H]([C@H](C)[C@@H](O)[C@@H](C)C=CC=C(C)C(=O)NC(C3=O)=C3NC5(CCN(CC(C)C)CC5)N=C13)O)C(=O)C2=4)O |t:10,31,33,&1:7,12,15,17,22,24,25,27,29| |
| InChi Key | ATEBXHFBFRCZMA-NYGPAKPVSA-N |
| InChi Code | InChI=1S/C46H62N4O11/c1-22(2)21-50-18-16-46(17-19-50)48-34-31-32-39(54)28(8)42-33(31)43(56)45(10,61-42)59-20-15-30(58-11)25(5)41(60-29(9)51)27(7)38(53)26(6)37(52)23(3)13-12-14-24(4)44(57)47-36(40(32)55)35(34)49-46/h12-15,20,22-23,25-27,30,37-38,41,49,52-54H,16-19,21H2,1-11H3,(H,47,57)/b13-12+,20-15+,24-14+/t23-,25+,26+,27+,30-,37-,38+,41+,45-/m0/s1 |
| Chemical Name | Rifamycin XIV, 1',4-didehydro-1-deoxy-1,4-dihydro-5'-(2-methylpropyl)-1-oxo- |
| Synonyms | Ansamycin; Rifabutin; LM-427; LM 427; LM427; Mycobutin; Rifabutina; |
| HS Tariff Code | 2934.99.03.00 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | Antibacterial |
| ln Vitro | Rifabutin is primarily prescribed as an antibiotic with bactericidal properties to treat tuberculosis. Its action on bacteria stems from its semi-synthetic derivative, rifamycin S., which blocks RNA polymerase in a DNA-dependent manner. It works well against a variety of bacteria, including Gram-positive and Gram-negative bacteria, Mycobacterium tuberculosis, M. leprae, and M. avium intracellulare. It is particularly effective against highly resistant mycobacteria. Antibiotic and antitumor drug rifabutin. Rifabutin inhibits the bacterial RNA polymerase, increases ubiquitination and protein degradation, and tampers with the HSP-90 molecular chaperone. |
| ln Vivo | Drug interactions between rifamycins and highly active antiretroviral therapy (HAART) have raised concerns in the treatment of human immunodeficiency virus (HIV)-infected patients with tuberculosis. We conducted a study of this interaction by measuring serum drug levels of all HIV-infected patients with tuberculosis who were admitted to A. G. Holley State Tuberculosis Hospital (Florida) from October 1997 through December 1998, who were concomitantly treated with rifabutin and HAART. All 25 patients studied became culture-negative within 2 months of initiation of therapy for tuberculosis and remained negative for a median of 13 months follow-up after completion of therapy. HIV viral loads (mean+/-SEM) decreased significantly from 4.95+/-0.21 log10 copies/mL before initiation of HAART to 2.77+/-0.07 log10 copies/mL before discharge (P<.001); 20 of 25 patients achieved viral loads of <500copies/mL. In summary, the concomitant use of rifabutin and HAART can lead to successful treatment of HIV-infected patients with tuberculosis without increased side effects[5]. |
| Enzyme Assay | Rifabutin shows good in vitro activity against H. pylori. Mean H. pylori rifabutin resistance rate (calculated from 11 studies including 2982 patients) was 1.3% (95% confidence interval = 0.9-1.7%). When only studies including patients naïve to H. pylori eradication treatment were considered, this figure was even lower (0.6%). On the other hand, higher values of rifabutin resistance were calculated (1.59%) when only post-treatment patients were considered. Overall, mean H. pylori eradication rate (intention-to-treat analysis) with rifabutin-containing regimens (1008 patients) was 73% (67-79%). Respective cure rates for second-line (223 patients), third-line (342 patients) and fourth/fifth-line (95 patients) rifabutin therapies were 79% (67-92%), 66% (55-77%) and 70% (60-79%) respectively. For treating H. pylori infection, almost all studies have administered rifabutin 300 mg/day; this dose seems to be more effective than 150 mg/day. The ideal length of treatment remains unclear, but 10- to 12-day regimens are generally recommended. The mean rate of adverse effects was 22% (19-25%). Myelotoxicity is the most significant, although this complication was rare. Until now, all patients have recovered of leucopenia uneventfully in a few days, and there have been no reports of infection or other adverse outcomes related to it[2]. |
| Animal Protocol | One hundred subjects were included. The indications for rifabutin (RFB) use wereRifampin (RMP)-related AE (57%), con- current antiretroviral therapy (21%), potential/actual interaction with other medications (14%), and as part of an alternative regimen in liver disease (8%). Nineteen patients experienced an AE while taking RFB. Among patients with a prior RMP-related AE, 80% of whom were successfully treated with RFB, only a dermatologic AE was associated with subsequent RFB intolerance. |
| References |
[1]. Effect of rifampin and rifabutin on the pharmacokinetics of lersivirine and effect of lersivirine on the pharmacokinetics of rifabutin and 25-o-desacetyl-rifabutin in healthy subjects. Antimicrob Agents Chemother. 2012 Aug;56(8):4303-9. [2]. Fourth-line rescue therapy with rifabutin in patients with three Helicobacter pylori eradication failures. Aliment Pharmacol Ther. 2012 Apr;35(8):941-7. [3]. Review article: rifabutin in the treatment of refractory Helicobacter pylori infection. Aliment Pharmacol Ther. 2012 Jan;35(2):209-21. [4]. Experience with rifabutin replacing rifampin in the treatment of tuberculosis. Int J Tuberc Lung Dis. 2011 Nov;15(11):1485-9, i. [5]. Use of rifabutin with protease inhibitors for human immunodeficiency virus-infected patients with tuberculosis. Clin Infect Dis. 2000 May;30(5):779-83. |
| Additional Infomation |
Rifampin is an antibacterial prescription medicine approved by the U.S. Food and Drug Administration (FDA) for the treatment of tuberculosis (TB). Rifampin is also FDA-approved to treat people who carry Neisseria meningitidis bacteria but have no symptoms of disease.
TB can be an opportunistic infection (OI) of HIV.
A broad-spectrum antibiotic that is being used as prophylaxis against disseminated Mycobacterium avium complex infection in HIV-positive patients. Rifabutin is a Rifamycin Antimycobacterial. Rifabutin is a rifamycin antibiotic that is similar in structure and activity to rifampin and rifapentine and which is used largely in the prevention of Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection. Rifabutin is associated with transient and asymptomatic elevations in serum aminotransferase and is a likely cause of clinically apparent, acute liver disease. Rifabutin is a semisynthetic ansamycin antibiotic with potent antimycobacterial properties. Rifabutin inhibits bacterial DNA-dependent RNA polymerase, thereby suppressing the initiation of RNA formation and leading to inhibition of RNA synthesis and transcription. Drug Indication For the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection. Rifabutin is indicated for the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced human immunodeficiency virus (HIV) infection. /Included in US product labeling/. Rifabutin also has in vitro activity against many strains of Mycobacterium tuberculosis. However, there is no evidence that rifabutin is effective as a prophylactic agent for tuberculosis. Isoniazid and rifabutin may be given concurrently for the prophylaxis of tuberculosis and mycobacterium avium complex, respectively. Cross-resistance between rifampin and rifabutin is commonly observed with mycobacterium avium complex isolates that are highly resistant to rifampin. /Included in US product labeling/ View More
Pharmacodynamics Absorption Rifabutin is readily absorbed from the gastrointestinal tract, with an absolute bioavailability averaging 20%. Route of Elimination A mass-balance study in three healthy adult volunteers with 14C-labeled rifabutin showed that 53% of the oral dose was excreted in the urine, primarily as metabolites. About 30% of the dose is excreted in the feces. Metabolism / Metabolites Hepatic. Of the five metabolites that have been identified, 25-O-desacetyl and 31-hydroxy are the most predominant. The former metabolite has an activity equal to the parent drug and contributes up to 10% to the total antimicrobial activity. iological Half-Life 45 (± 17) hours Mechanism of Action Rifabutin acts via the inhibition of DNA-dependent RNA polymerase in gram-positive and some gram-negative bacteria, leading to a suppression of RNA synthesis and cell death. Rifabutin inhibits DNA-dependent RNA polymerase in susceptible strains of Escherichia coli and Bacillus subtilis, but not in mammalian cells. Rifabutin does not inhibit this enzyme is resistant strains of Escherichia coli. It is not known whether rifabutin inhibits DNA-dependent RNA polymerase in Mycobacterium avium or in Mycobacterium intracellulare, which constitute Mycobacterium avium complex. |
Solubility Data
| Solubility (In Vitro) |
DMSO : 50~100 mg/mL (59.03~118.06 mM) Ethanol : ~100 mg/mL |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.95 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 10% DMSO+40% PEG300+5% Tween-80+45% Saline (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1806 mL | 5.9032 mL | 11.8064 mL | |
| 5 mM | 0.2361 mL | 1.1806 mL | 2.3613 mL | |
| 10 mM | 0.1181 mL | 0.5903 mL | 1.1806 mL |