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Identification
NameRifabutin
Accession NumberDB00615  (APRD00094)
TypeSmall Molecule
GroupsApproved
Description

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

Structure
Thumb
Synonyms
SynonymLanguageCode
1,4-Dihydro-1-deoxy-1',4-didehydro-5'-(2-methylpropyl)-1-oxorifamycin xivNot AvailableNot Available
4-Deoxo-3,4-(2-spiro(N-isobutyl-4-piperidyl)-2,5-dihydro-1H-imidazo)-rifamycin SNot AvailableNot Available
4-N-Isobutylspiropiperidylrifamycin SNot AvailableNot Available
AnsamicinNot AvailableIS
AnsamycinNot AvailableIS
Mycobutin (tn)Not AvailableNot Available
RifabutinGermanINN
RifabutinaSpanish/ItalianINN/DCIT
RifabutineFrenchINN
RifabutinumLatinINN
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Mycobutincapsule150 mgoralPharmacia and Upjohn Company1992-12-23Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Mycobutincapsule150 mgoralPhysicians Total Care, Inc.1995-03-15Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Rifabutincapsule150 mgoralGreenstone LLC2014-04-07Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Mycobutincapsule150 mgoralPfizer Canada IncNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Rifabutincapsule150 mgoralLupin Pharmaceuticals, Inc.2014-03-26Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Over the Counter ProductsNot Available
International Brands
NameCompany
AnsatipinPfizer
AnsatipineSERB
RibutinLupin
Brand mixturesNot Available
SaltsNot Available
Categories
CAS number72559-06-9
WeightAverage: 847.0047
Monoisotopic: 846.441508846
Chemical FormulaC46H62N4O11
InChI KeyATEBXHFBFRCZMA-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
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[23.6.1.1⁴,⁷.0⁵,³¹.0²⁶,³⁰]tritriacontane-28,4'-piperidin]-1(31),2,4,9,19,21,25,29-octaen-13-yl acetate
SMILES
CO[C@H]1\C=C\O[C@@]2(C)OC3=C(C2=O)C2=C(C(O)=C3C)C(=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)=C1NC3(CCN(CC3)CC(C)C)N=C21
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as macrolactams. These are cyclic amides of amino carboxylic acids, having a 1-azacycloalkan-2-one structure, or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring. They are nitrogen analogues (the a nitrogen atom replacing the o atom of the cyclic carboxylic acid group ) of the naturally occurring macrolides.
KingdomOrganic compounds
Super ClassPhenylpropanoids and polyketides
ClassMacrolactams
Sub ClassNot Available
Direct ParentMacrolactams
Alternative Parents
Substituents
  • Naphthofuran
  • Macrolactam
  • Naphthalene
  • Azaspirodecane
  • Benzofuran
  • Aryl alkyl ketone
  • Aryl ketone
  • Benzenoid
  • Piperidine
  • Acetate salt
  • Vinylogous amide
  • Vinylogous acid
  • 3-imidazoline
  • Tertiary aliphatic amine
  • Tertiary amine
  • Secondary carboxylic acid amide
  • Secondary alcohol
  • Polyol
  • Lactam
  • Ketone
  • Ketimine
  • Carboxylic acid ester
  • Carboxamide group
  • Oxacycle
  • Azacycle
  • Organoheterocyclic compound
  • Organic 1,3-dipolar compound
  • Propargyl-type 1,3-dipolar organic compound
  • Ether
  • Dialkyl ether
  • Carboxylic acid derivative
  • Carboxylic acid amide
  • Acetal
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Imine
  • Carbonyl group
  • Amine
  • Alcohol
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection.
PharmacodynamicsRifabutin 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 actionRifabutin 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.
AbsorptionRifabutin is readily absorbed from the gastrointestinal tract, with an absolute bioavailability averaging 20%.
Volume of distributionNot Available
Protein binding85%
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.

SubstrateEnzymesProduct
Rifabutin
27-O-demethylrifabutinDetails
Rifabutin
Not Available
25-O-desacetyl rifabutinDetails
Rifabutin
Not Available
31-hydroxy rifabutinDetails
Route of eliminationA 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 life45 (± 17) hours
Clearance
  • 0.69 +/- 0.32 L/hr/kg
ToxicityLD50 = 4.8 g/kg (mouse, male)
Affected organisms
  • Enteric bacteria and other eubacteria
  • Mycobacterium tuberculosis
  • Mycobacterium leprae
  • Mycobacterium avium
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.5507
Blood Brain Barrier-0.9921
Caco-2 permeable-0.7072
P-glycoprotein substrateSubstrate0.9612
P-glycoprotein inhibitor IInhibitor0.5415
P-glycoprotein inhibitor IIInhibitor0.6516
Renal organic cation transporterNon-inhibitor0.8178
CYP450 2C9 substrateNon-substrate0.819
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateSubstrate0.745
CYP450 1A2 substrateNon-inhibitor0.9046
CYP450 2C9 substrateNon-inhibitor0.9071
CYP450 2D6 substrateNon-inhibitor0.9231
CYP450 2C19 substrateNon-inhibitor0.9026
CYP450 3A4 substrateNon-inhibitor0.8308
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8909
Ames testNon AMES toxic0.6724
CarcinogenicityNon-carcinogens0.9195
BiodegradationNot ready biodegradable0.9687
Rat acute toxicity2.5143 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.946
hERG inhibition (predictor II)Inhibitor0.5416
Pharmacoeconomics
Manufacturers
  • Pharmacia and upjohn co
Packagers
Dosage forms
FormRouteStrength
Capsuleoral150 mg
Prices
Unit descriptionCostUnit
Mycobutin 150 mg capsule13.01USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubilityMinimally soluble (0.19 mg/mL)Not Available
logP4.1Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.017 mg/mLALOGPS
logP4.25ALOGPS
logP4.19ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)7.93ChemAxon
pKa (Strongest Basic)8.62ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count13ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area205.55 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity232.64 m3·mol-1ChemAxon
Polarizability90.72 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General ReferenceNot Available
External Links
ATC CodesJ04AB04
AHFS Codes
  • 08:16.04
PDB EntriesNot Available
FDA labelDownload (69.5 KB)
MSDSDownload (58.4 KB)
Interactions
Drug Interactions
Drug
AtazanavirAtazanavir may increase serum concentrations of the active metabolite(s) of Rifabutin. Atazanavir may increase the serum concentration of Rifabutin.
BoceprevirBoceprevir may increase the serum concentration of Rifabutin. Rifabutin may decrease the serum concentration of Boceprevir.
DarunavirDarunavir may increase serum concentrations of the active metabolite(s) of Rifabutin. Darunavir may increase the serum concentration of Rifabutin. Rifabutin may increase the serum concentration of Darunavir.
EtravirineMay decrease the serum concentration of Etravirine.
FosamprenavirFosamprenavir may increase serum concentrations of the active metabolite(s) of Rifabutin. Fosamprenavir may increase the serum concentration of Rifabutin. Rifabutin may increase the serum concentration of Fosamprenavir.
IndinavirIndinavir may increase serum concentrations of the active metabolite(s) of Rifabutin. Indinavir may increase the serum concentration of Rifabutin. Rifabutin may decrease the serum concentration of Indinavir.
LedipasvirMay decrease the serum concentration of Sofosbuvir.
LopinavirLopinavir may increase serum concentrations of the active metabolite(s) of Rifabutin. Lopinavir may increase the serum concentration of Rifabutin. Rifabutin may increase the serum concentration of Lopinavir.
NelfinavirNelfinavir may increase serum concentrations of the active metabolite(s) of Rifabutin. Nelfinavir may increase the serum concentration of Rifabutin. Rifabutin may decrease the serum concentration of Nelfinavir.
NevirapineNevirapine may decrease the serum concentration of Rifabutin. Nevirapine may increase the serum concentration of Rifabutin. Rifabutin may decrease the serum concentration of Nevirapine.
RaltegravirMay decrease the serum concentration of Raltegravir. Specifically, minimum serum concentrations (Cmin) may be reduced. Total raltegravir exposure (i.e., AUC) may be increased.
RilpivirineMay decrease the serum concentration of Rilpivirine.
RitonavirRitonavir may increase serum concentrations of the active metabolite(s) of Rifabutin. Ritonavir may increase the serum concentration of Rifabutin.
SaquinavirSaquinavir may increase serum concentrations of the active metabolite(s) of Rifabutin. Rifabutin may decrease the serum concentration of Saquinavir. Saquinavir may increase the serum concentration of Rifabutin.
SofosbuvirMay decrease the serum concentration of Sofosbuvir.
TelaprevirMay decrease the serum concentration of Telaprevir. Telaprevir may increase the serum concentration of Rifabutin.
TipranavirTipranavir may increase serum concentrations of the active metabolite(s) of Rifabutin. Tipranavir may increase the serum concentration of Rifabutin.
Food Interactions
  • High-fat meals slow the rate of absorption.
  • Take with food to reduce irritation.

Targets

1. DNA-directed RNA polymerase subunit alpha

Kind: protein

Organism: Escherichia coli (strain K12)

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
DNA-directed RNA polymerase subunit alpha P0A7Z4 Details

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 subunit beta

Kind: protein

Organism: Escherichia coli (strain K12)

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
DNA-directed RNA polymerase subunit beta P0A8V2 Details

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'

Kind: protein

Organism: Escherichia coli (strain K12)

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
DNA-directed RNA polymerase subunit beta' P0A8T7 Details

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

Kind: protein

Organism: Human

Pharmacological action: no

Actions: other/unknown

Components

Name UniProt ID Details
Heat shock protein HSP 90-alpha P07900 Details

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

Kind: protein

Organism: Human

Pharmacological action: no

Actions: other/unknown

Components

Name UniProt ID Details
Endoplasmin P14625 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inducer

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

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

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Drug created on June 13, 2005 07:24 / Updated on January 20, 2014 11:32