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HomeProduct name listRifabutin

Rifabutin

Synonym(s):Ansamycin;Ansatipine (Farmitalia);LM-427;Mycobutin (Farmitalia);Rifabutin

  • CAS NO.:72559-06-9
  • Empirical Formula: C46H62N4O11
  • Molecular Weight: 847
  • MDL number: MFCD00866816
  • EINECS: 615-780-3
  • SAFETY DATA SHEET (SDS)
  • Update Date: 2024-11-05 19:05:58
Rifabutin Structural

What is Rifabutin?

Absorption

Rifabutin is readily absorbed from the gastrointestinal tract, with an absolute bioavailability averaging 20%.

Toxicity

LD50 = 4.8 g/kg (mouse, male)

Description

Rifabutin, a rifamycin antibacterial derivative, is the first agent approved and introduced for the prevention of Mycobacterium avium complex (MAC) in AIDS patients. It is also indicated in combination chemotherapy for the prophylaxis and treatment of MAC infections in HIV positive patients and for newly diagnosed and chronic tuberculosis.

Chemical properties

Red-Brown Powder

Originator

Archifar (Italy)

The Uses of Rifabutin

Rifamycins are antibiotics that inhibit DNA-dependent RNA polymerases and are usually bactericidal against Gram-positive bacteria but bacteriostatic against Gram-negative bacteria. Rifamycins are also effective against Mycobacterium species, including M. tuberculosis. Rifabutin is a broad-spectrum rifamycin antibiotic that has applications against tuberculosis, H. pylori, M. avium complex, Chlamydia, and other bacteria. It is also useful in co-infections with human immunodeficiency virus, including tuberculosis.

The Uses of Rifabutin

Semisynthetic derivative of Rifamycin S that inhibits nucleic acid synthesis. An antibacterial (tuberculostatic).

The Uses of Rifabutin

Antibiotic;RNA-polymerase inhibitor

Background

A broad-spectrum antibiotic that is being used as prophylaxis against disseminated Mycobacterium avium complex infection in HIV-positive patients.

Indications

For the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection.

What are the applications of Application

Rifabutin is a semisynthetic antibacterial derivative of Rifamycin S

Indications

Rifabutin (Mycobutin), an antibiotic related to rifampin, shares its mechanism of action, that is, inhibition of RNA polymerase. Rifabutin has significant activity in vitro and in vivo against M. avium-intracellular complex (MAC) isolates from both HIV-infected and non–HIV-infected individuals. It has better activity against MAC organisms than rifampin. Rifabutin is active against M. tuberculosis, including some rifampinresistant strains, such as M.leprae and M.fortuitum. It has a spectrum of activity against gram-positive and gramnegative organisms similar to that of rifampin. The molecular basis for resistance to rifabutin is shared by both rifampin and rifabutin; this explains the virtually complete cross-resistance that occurs between these drugs.

Definition

ChEBI: Rifabutin is a member of rifamycins. It has a role as an antitubercular agent.

brand name

Mycobutin (Pharmacia & Upjohn).

Antimicrobial activity

The activity is similar to that of rifampicin, but it is more active against the Mycobacterium avium complex (MIC 0.01–2 mg/L) and several other atypical mycobacteria. It inhibits the replication of human immunodeficiency virus 1 (HIV-1) in concentrations (10 mg/L) that are not toxic to lymphoid cells, but no efficacy on HIV infections has been demonstrated.

Acquired resistance

The frequency of spontaneously resistant mutants in several bacterial species, including M. tuberculosis, M. leprae, Staphylococcus aureus and Chlamydia trachomatis, is somewhat lower than with rifampicin.

Pharmaceutical Applications

Rifabutine; ansamycin. Molecular weight: 847.02.
A semisynthetic spiropiperidyl derivative of rifamycin S, available for oral administration. It is slightly soluble in water and soluble in organic solvents.

Biochem/physiol Actions

Rifabutin is an antibiotic; antitumor. Rifabutin interferes with HSP-90 molecular chaperone, enhances ubiquitination and protein degradation, and inactivates bacterial RNA polymerase.

Pharmacokinetics

Rifabutin is an antibiotic that inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme. It is bactericidal and has a very broad spectrum of activity against most gram-positive and gram-negative organisms (including Pseudomonas aeruginosa) and specifically Mycobacterium tuberculosis. Because of rapid emergence of resistant bacteria, use is restricted to treatment of mycobacterial infections and a few other indications. Rifabutin is well absorbed when taken orally and is distributed widely in body tissues and fluids, including the CSF. It is metabolized in the liver and eliminated in bile and, to a much lesser extent, in urine, but dose adjustments are unnecessary with renal insufficiency.

Pharmacokinetics

Oral absorption:12–20%
Cmax 300 mg oral :0.38 mg/L after 3.3 h
Plasma half-life:16 h
Volume of distribution:9.3 L/kg
Plasma protein binding: 85%
absorption and distribution
Oral absorption is rapid but incomplete, with considerable interpatient variation. It is well distributed, concentrations in many organs being higher than that in plasma. The average concentration in lungs is 6.5 times the simultaneous plasma concentration.
Metabolism and excretion
Rifabutin is mainly metabolized to the active desacetyl derivative, although several other oxidation products have been detected in urine, where some 10% of the dose is eliminated. About 30–50% of the dose can be recovered from the feces. Elimination from plasma is biphasic, with a terminal half-life of 45 h. The drug is a weak inducer of hepatic enzymes. The rate of metabolism increases, and the plasma area under the concentration–time curve (AUC) declines as the treatment continues.

Pharmacology

Rifabutin is well absorbed orally, and peak plasma concentrations are reached in 2 to 3 hours. Because of its lipophilicity, rifabutin achieves a 5- to 10-fold higher concentration in tissues than in plasma. The drug has a half-life range of 16 to 96 hours and is eliminated in urine and bile.
Rifabutin appears as effective as rifampin in the treatment of drug-susceptible tuberculosis and is used in the treatment of latent tuberculosis infection either alone or in combination with pyrazinamide. Clinical use of rifabutin has increased in recent years, especially in the treatment of HIV infection. It is a less potent inducer of cytochrome 450 enzymes pathways than rifampin and results in less drug interaction with the protease inhibitors and nonnucleoside reverse transcriptase inhibitors. Rifabutin is therefore commonly substituted for rifampin in the treatment of tuberculosis in HIV-infected patients. Another important use of rifabutin in the HIV-infected population is prevention and treatment of disseminated MAC.

Clinical Use

Prevention of infections with M. avium complex in AIDS patients
Treatment of non-tuberculous mycobacterial disease (in combination with other agents)
Rifabutin in combination with other agents has been proposed as a rescue therapy after Helicobacter pylori treatment failures.Although some efficacy has been observed in the treatment of tuberculosis, its use for this condition is not recommended.

Clinical Use

Rifabutin, the spiroimidazopiperidyl derivative of rifamycin B was approved in the United States for the prophylaxis of disseminated MAC in AIDS patients on the strength of clinical trials establishing its effectiveness. The activity of rifabutin against MAC organisms greatly exceeds that of rifamycin. This rifamycin derivative is not effective, however, as monotherapy for existing disseminated MAC disease. Rifabutin is a very lipophilic compound with a high affinity for tissues. Its elimination is distribution limited, with a half-life averaging 45 hours (range, 16 69 hours). Approximately 50% of an orally administered dose of rifabutin is absorbed, but the absolute oral bioavailability is only about 20%. Extensive first-pass metabolism and significant biliary excretion of the drug occur, with about 35% and 53% of the orally administered dose excreted, largely as metabolites, in the feces and urine, respectively. Despite its greater potency against M. tuberculosis in vitro, rifabutin is considered inferior to rifampin for the short-term therapy of tuberculosis because of its significantly lower plasma concentrations.
Although rifabutin is believed to cause less hepatotoxicityand induction of cytochrome P450 enzymes than rifampin,these properties should be borne in mind when the drug is usedprophylactically. Rifabutin and its metabolites are highly coloredcompounds that can discolor skin, urine, tears, feces, etc.

Side Effects

Rash (4% of patients), gastrointestinal intolerance (3%) and neutropenia (2%) are fairly common and may require discontinuation of treatment. Uveitis and general arthralgia are rare with a 300 mg dosage, but frequent with higher dosages, especially with concomitant use of fluconazole or macrolide antibiotics.

Side Effects

The adverse effects that most frequently result in discontinuation of rifabutin include GI intolerance, rash, and neutropenia. Rifabutin levels will be increased with concurrent administration of fluconazole and clarithromycin, resulting in anterior uveitis, polymyalgia syndrome, and a yellowish-tan discoloration of the skin (pseudojaundice). Other adverse reactions are similar to those of rifampin, such as hepatitis, red-orange discoloration of body fluids, and drug interactions due to effects on the hepatic P450 cytochrome enzyme system.

Drug interactions

Potentially hazardous interactions with other drugs
Anti-arrhythmics: metabolism of disopyramide, and propafenone accelerated; concentration of dronedarone reduced.
Antibacterials: increased risk of side effects with azithromycin; clarithromycin and other macrolides increase concentration of rifabutin, resulting in increased risk of uveitis - reduce rifabutin dose; reduced concentration of dapsone and clarithromycin.
Anticoagulants: reduced anticoagulant effect of coumarins.
Antidiabetics: reduced antidiabetic effect of tolbutamide; possibly reduced antidiabetic effect with sulphonylureas.
Antiepileptics: reduced concentration of fosphenytoin, phenytoin and carbamazepine.
Antifungals: fluconazole, triazoles, posaconazole and voriconazole increase the concentration of rifabutin resulting in increased risk of uveitis - reduce rifabutin dose; rifabutin reduces concentration of posaconazole, voriconazole and itraconazole - increase voriconazole dose, avoid with isavuconazole and itraconazole.
Antipsychotics: possibly reduced aripiprazole concentration - increase dose of aripiprazole.
Antivirals: atazanavir darunavir, fosamprenavir, saquinavir and tipranavir and possibly nevirapine increase concentration of rifabutin - halve or reduce dose of rifabutin; efavirenz reduces the concentration of rifabutin - increase dose of rifabutin; concentration of both drugs reduced with etravirine; indinavir increases rifabutin concentration - avoid; concentration of indinavir reduced - increase indinavir dose; concentration of elvitegravir reduced and active metabolite of rifabutin increased - reduce dose of rifabutin; concentration of rilpivirine reduced - increase rilpivirine dose to 50mg once daily; ritonavir increases the concentration of rifabutin resulting in increased risk of uveitis - reduce rifabutin dose; concentration of saquinavir reduced and concentration of rifabutin increased - reduce rifabutin dose; concentration of daclatasvir and simeprevir possibly reduced - avoid; avoid with ledipasvir, sofosbuvir and telaprevir.
Atovaquone: concentration of atovaquone reduced (possible therapeutic failure of atovaquone).
Ciclosporin: possibly reduced ciclosporin levels.
Cobicistat: concentration of cobicistat reduced - adjust cobicistat dose.
Corticosteroids: reduced level of corticosteroids - double steroid dose. Give as twice daily dosage.
Cytotoxics: possibly reduced concentration of axitinib (increase axitinib dose), bosutinib, cabazitaxel, ceritinib, crizotinib, lapatinib, olaparib, panobinostat, ponatinib and vemurafenib - avoid.
Guanfacine: concentration of guanfacine possibly reduced - increase dose of guanfacine.
Hormone antagonists: concentration of abiraterone possibly reduced - avoid.
Ivacaftor: concentration of ivacaftor possibly reduced - avoid.
Oestrogens and progestogens: reduced contraceptive effect due to increased metabolism.
Sirolimus: reduced sirolimus concentration - avoid.
Tacrolimus: possibly reduced tacrolimus trough concentration.
Ulipristal: possibly reduced contraceptive effect - avoid.

Metabolism

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.

Metabolism

Rifabutin is rapidly metabolised in the liver by the cytochrome P450 isoenzyme CYP3A4 mainly to active 25-O-deacetyl and 31-hydroxy metabolites. Rifabutin induces its own metabolism resulting in a lower AUC after 4 weeks of continuous treatment than after the first few doses.
About 53% of a dose is found in the urine, mainly as metabolites and about 30% of a dose is excreted in the faeces.

Properties of Rifabutin

Melting point: 169-171°C
Boiling point: 969.6±65.0 °C(Predicted)
Density  1.33±0.1 g/cm3(Predicted)
storage temp.  Keep in dark place,Inert atmosphere,Store in freezer, under -20°C
solubility  DMSO: >5mg/mL
form  powder
pka 3.31±0.70(Predicted)
color  Dark Red to Dark Purple
Water Solubility  0.19g/L(temperature not stated)
Stability: Hygroscopic and Light Sensitive
CAS DataBase Reference 72559-06-9

Safety information for Rifabutin

Signal word Warning
Pictogram(s)
ghs
Exclamation Mark
Irritant
GHS07
GHS Hazard Statements H302:Acute toxicity,oral
H319:Serious eye damage/eye irritation
Precautionary Statement Codes P305+P351+P338:IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

Computed Descriptors for Rifabutin

InChIKey ATEBXHFBFRCZMA-VXTBVIBXSA-N

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