Banner
targets (5) enzymes (2)
for drugs
Identification
Name Rifabutin
Accession Number DB00615 (APRD00094)
Type small molecule
Groups approved
Description

A broad-spectrum antibiotic that is being used as prophylaxis against disseminated Mycobacterium avium complex infection in HIV-positive patients. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Ansatipin
  • Ansatipine
  • Antibiotic LM 427
  • RBT
  • Rifabutina [Spanish]
  • Rifabutine [French]
  • Rifabutinum [Latin]
Brand names
  • Alfacid
  • Ansamycin
  • Mycobutin
Brand name mixtures Not Available
Categories
  • Anti-Bacterial Agents
  • Antibiotics, Antitubercular
CAS number 72559-06-9
Weight Average: 847.0047
Monoisotopic: 846.441508846
Chemical Formula C46H62N4O11
InChI Key InChIKey=ATEBXHFBFRCZMA-VXTBVIBXSA-N
InChI
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
Plain Text
IUPAC Name
(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-1'-(2-methylpropyl)-6,23,32-trioxo-8,33-dioxa-24,27,29-triazaspiro[pentacyclo[23.6.1.1^{4,7}.0^{5,31}.0^{26,30}]tritriacontane-28,4'-piperidin]-1,3,5(31),9,19,21,25,29-octaen-13-yl acetate
SMILES
CO[C@H]1\C=C\O[C@@]2(C)OC3=C(C)C(O)=C4C(=O)C(NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)=C1NC5(CCN(CC(C)C)CC5)N=C1C4=C3C2=O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Ansamycins
  • Lactams
Substructures
  • Ansamycins
  • Carboxylic Acids and Derivatives
  • Benzofurans
  • Hydroxy Compounds
  • Alkanes and Alkenes
  • Acetates
  • Acetals and Derivatives
  • Phenols and Derivatives
  • Amino Ketones
  • Ethers
  • Benzene and Derivatives
  • Methoxyphenols
  • Aliphatic and Aryl Amines
  • Imidazoles
  • Phenethylamines
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Carboxamides and Derivatives
  • Lactams
  • Imines
  • Benzoyl Derivatives
  • Alcohols and Polyols
  • Phenyl Esters
  • Piperidines
  • Ketones
Pharmacology
Indication For the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection.
Pharmacodynamics 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.
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.
Absorption Rifabutin is readily absorbed from the gastrointestinal tract, with an absolute bioavailability averaging 20%.
Volume of distribution Not Available
Protein binding 85%
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.

Enzyme Metabolite Reaction Km Vmax
Cytochrome P450 3A4 27-O-demethylrifabutin 27-O-demethylation 10.9 0.1
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.
Half life 45 (± 17) hours
Clearance
  • 0.69 +/- 0.32 L/hr/kg
Toxicity LD50 = 4.8 g/kg (mouse, male)
Affected organisms
  • Enteric bacteria and other eubacteria
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Pharmacia and upjohn co
Packagers
Dosage forms
Form Route Strength
Capsule Oral
Prices
Unit description Cost Unit
Mycobutin 150 mg capsule 13.01 USD capsule
Patents Not Available
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
water solubility Minimally soluble (0.19 mg/mL) PhysProp
logP 4.1 PhysProp
Predicted Properties
Property Value Source
water solubility 1.70e-02 g/l ALOGPS
logP 4.25 ALOGPS
logP 4.15 ChemAxon Molconvert
logS -4.70 ALOGPS
pKa 12.63 ChemAxon Molconvert
hydrogen acceptor count 13 ChemAxon Molconvert
hydrogen donor count 5 ChemAxon Molconvert
polar surface area 205.55 ChemAxon Molconvert
rotatable bond count 5 ChemAxon Molconvert
refractivity 232.64 ChemAxon Molconvert
polarizability 90.72 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00424 Link_out
KEGG Compound C07235 Link_out
PubChem Compound 6323490 Link_out
PubChem Substance 46506468 Link_out
ChemSpider 4883445 Link_out
ChEBI 8857 Link_out
ChEMBL 8857 Link_out
Therapeutic Targets Database DAP000656 Link_out
PharmGKB PA451249 Link_out
HET RBT Link_out
Drug Product Database 2063786 Link_out
RxList http://www.rxlist.com/cgi/generic2/rifabutin.htm Link_out
Drugs.com http://www.drugs.com/cdi/rifabutin.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Rifabutin Link_out
ATC Codes
  • J04AB04
AHFS Codes
  • 08:16.04
PDB Entries Not Available
FDA label show (69.5 KB)
MSDS show (58.4 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • High-fat meals slow the rate of absorption.
  • Take with food to reduce irritation.
Targets

1. DNA-directed RNA polymerase alpha chain

Pharmacological action: yes
Actions: inhibitor

DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. This subunit plays an important role in subunit assembly since its dimerization is the first step in the sequential assembly of subunits to form the holoenzyme

Organism class: bacterial
UniProt ID: P0A7Z4 Link_out
Gene: rpoA
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Maddix DS, Tallian KB, Mead PS: Rifabutin: a review with emphasis on its role in the prevention of disseminated Mycobacterium avium complex infection. Ann Pharmacother. 1994 Nov;28(11):1250-4. Pubmed

2. DNA-directed RNA polymerase beta chain

Pharmacological action: yes
Actions: inhibitor

DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates

Organism class: bacterial
UniProt ID: P0A8V2 Link_out
Gene: rpoB
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Maddix DS, Tallian KB, Mead PS: Rifabutin: a review with emphasis on its role in the prevention of disseminated Mycobacterium avium complex infection. Ann Pharmacother. 1994 Nov;28(11):1250-4. Pubmed

3. DNA-directed RNA polymerase subunit beta'

Pharmacological action: yes
Actions: inhibitor

DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates

Organism class: bacterial
UniProt ID: P0A8T7 Link_out
Gene: rpoC Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Maddix DS, Tallian KB, Mead PS: Rifabutin: a review with emphasis on its role in the prevention of disseminated Mycobacterium avium complex infection. Ann Pharmacother. 1994 Nov;28(11):1250-4. Pubmed

4. Heat shock protein HSP 90-alpha

Pharmacological action: no
Actions: other/unknown

Molecular chaperone. Has ATPase activity

Organism class: human
UniProt ID: P07900 Link_out
Gene: HSP90AA1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Schnaider T, Somogyi J, Csermely P, Szamel M: The Hsp90-specific inhibitor geldanamycin selectively disrupts kinase-mediated signaling events of T-lymphocyte activation. Cell Stress Chaperones. 2000 Jan;5(1):52-61. Pubmed
  2. Neckers L, Schulte TW, Mimnaugh E: Geldanamycin as a potential anti-cancer agent: its molecular target and biochemical activity. Invest New Drugs. 1999;17(4):361-73. Pubmed
  3. Srethapakdi M, Liu F, Tavorath R, Rosen N: Inhibition of Hsp90 function by ansamycins causes retinoblastoma gene product-dependent G1 arrest. Cancer Res. 2000 Jul 15;60(14):3940-6. Pubmed
  4. Munster PN, Srethapakdi M, Moasser MM, Rosen N: Inhibition of heat shock protein 90 function by ansamycins causes the morphological and functional differentiation of breast cancer cells. Cancer Res. 2001 Apr 1;61(7):2945-52. Pubmed
  5. Yang J, Yang JM, Iannone M, Shih WJ, Lin Y, Hait WN: Disruption of the EF-2 kinase/Hsp90 protein complex: a possible mechanism to inhibit glioblastoma by geldanamycin. Cancer Res. 2001 May 15;61(10):4010-6. Pubmed

5. Endoplasmin

Pharmacological action: no
Actions: other/unknown

Molecular chaperone that functions in the processing and transport of secreted proteins

Organism class: human
UniProt ID: P14625 Link_out
Gene: HSP90B1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Barzilay E, Ben-Califa N, Supino-Rosin L, Kashman Y, Hirschberg K, Elazar Z, Neumann D: Geldanamycin-associated inhibition of intracellular trafficking is attributed to a co-purified activity. J Biol Chem. 2004 Feb 20;279(8):6847-52. Epub 2003 Dec 1. Pubmed
  2. Chavany C, Mimnaugh E, Miller P, Bitton R, Nguyen P, Trepel J, Whitesell L, Schnur R, Moyer J, Neckers L: p185erbB2 binds to GRP94 in vivo. Dissociation of the p185erbB2/GRP94 heterocomplex by benzoquinone ansamycins precedes depletion of p185erbB2. J Biol Chem. 1996 Mar 1;271(9):4974-7. Pubmed
  3. Lawson B, Brewer JW, Hendershot LM: Geldanamycin, an hsp90/GRP94-binding drug, induces increased transcription of endoplasmic reticulum (ER) chaperones via the ER stress pathway. J Cell Physiol. 1998 Feb;174(2):170-8. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate, inducer

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
  2. Ekins S, Bravi G, Wikel JH, Wrighton SA: Three-dimensional-quantitative structure activity relationship analysis of cytochrome P-450 3A4 substrates. J Pharmacol Exp Ther. 1999 Oct;291(1):424-33. Pubmed

2. Cytochrome P450 1A2

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 13:41

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.