You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on DrugBank.
Identification
NameClofazimine
Accession NumberDB00845  (APRD00278)
TypeSmall Molecule
GroupsApproved, Investigational
Description

A fat-soluble riminophenazine dye used for the treatment of leprosy. It has been used investigationally in combination with other antimycobacterial drugs to treat Mycobacterium avium infections in AIDS patients. Clofazimine also has a marked anti-inflammatory effect and is given to control the leprosy reaction, erythema nodosum leprosum. (From AMA Drug Evaluations Annual, 1993, p1619)

Structure
Thumb
Synonyms
Clofazimin
Clofazimina
Clofazimine
Clofaziminum
Lamprene
Riminophenazine
External Identifiers
  • B 663
  • G 30320
  • NSC 141046
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
ClofozineAstraZeneca
HansepranAbbott
LamcoinPond's Chemical
LamprenNovartis
LamprèneNovartis
LampreneNovartis
Brand mixturesNot Available
SaltsNot Available
Categories
UNIID959AE5USF
CAS number2030-63-9
WeightAverage: 473.396
Monoisotopic: 472.122152138
Chemical FormulaC27H22Cl2N4
InChI KeyInChIKey=WDQPAMHFFCXSNU-BGABXYSRSA-N
InChI
InChI=1S/C27H22Cl2N4/c1-17(2)30-24-16-27-25(15-23(24)31-20-11-7-18(28)8-12-20)32-22-5-3-4-6-26(22)33(27)21-13-9-19(29)10-14-21/h3-17,31H,1-2H3/b30-24+
IUPAC Name
N,5-bis(4-chlorophenyl)-3-[(propan-2-yl)imino]-3,5-dihydrophenazin-2-amine
SMILES
CC(C)N=C1C=C2N(C3=CC=C(Cl)C=C3)C3=C(C=CC=C3)N=C2C=C1NC1=CC=C(Cl)C=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as phenazines and derivatives. These are polycyclic aromatic compounds containing a phenazine moiety, which is a linear tricyclic system that consists of a two benzene rings joined by a pyrazine ring.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassNaphthyridines
Sub ClassQuinoxalines
Direct ParentPhenazines and derivatives
Alternative Parents
Substituents
  • Phenazine
  • Substituted aniline
  • Halobenzene
  • Chlorobenzene
  • Aniline
  • Benzenoid
  • Pyrazine
  • Monocyclic benzene moiety
  • Aryl halide
  • Aryl chloride
  • Heteroaromatic compound
  • Secondary ketimine
  • Azacycle
  • Secondary amine
  • Hydrocarbon derivative
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of lepromatous leprosy, including dapsone-resistant lepromatous leprosy and lepromatous leprosy complicated by erythema nodosum leprosum.
PharmacodynamicsClofazimine exerts a slow bactericidal effect on Mycobacterium leprae (Hansen's bacillus). Clofazimine inhibits mycobacterial growth and binds preferentially to mycobacterial DNA. Clofazimine also exerts antiinflammatory properties in controlling erythema nodosum leprosum reactions. Clofazimine is highly lipophilic and tends to be deposited predominantly in fatty tissue and in cells of the reticuloendothelial system. It is taken up by macrophages throughout the body. Measurement of the minimum inhibitory concentration (MIC) of clofazimine against leprosy bacilli in vitro is not yet feasible. In the mouse footpad system, the multiplication of M.leprae is inhibited by introducing 0.0001%- 0.001% clofazimine in the diet. Although bacterial killing may begin shortly after starting the drug, it cannot be measured in biopsy tissues taken from patients for mouse footpad studies until approximately 50 days after the start of therapy.
Mechanism of actionAppears to preferentially bind to mycobacterial DNA leading to disruption of the cell cycle and eventually kills the bacterium. It may also bind to bacterial potassium transporters, thereby inhibiting their function. Lysophospholipids have been found to mediate the activity of this drug.
Related Articles
AbsorptionAbsorption varies from 45 to 62% following oral administration in leprosy patients. Bioavailability is approximately 70%. Food increases bioavailability and rate of absorption.
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic. Three metabolites have been identified - two conjugated and one unconjugated, however, it is not yet known whether these metabolites are pharmacologically active. Metabolite I is formed by hydrolytic dehalogenation of clofazimine, metabolite II presumably is formed by a hydrolytic deamination reaction followed by glucuronidation, and metabolite III appears to be a hydrated clofazimine glucuronide.

SubstrateEnzymesProduct
Clofazimine
Not Available
clofazimine glucuronideDetails
Route of eliminationNot Available
Half life10 days following a single dose, 70 days after long-term, high-dose therapy.
ClearanceNot Available
ToxicityOral, rabbit: LD50 = 3.3 g/kg; Oral, mouse: LD50 = > 4 g/kg. Severe abdominal symptoms have necessitated exploratory laparotomies in some patients on clofazimine therapy. Rare reports have included splenic infarction, bowel obstruction, and gastrointestinal bleeding. Deaths have been reported, following severe abdominal symptoms.
Affected organisms
  • Mycobacteria
  • Mycobacterium leprae
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9881
Blood Brain Barrier+0.7616
Caco-2 permeable+0.6769
P-glycoprotein substrateNon-substrate0.5905
P-glycoprotein inhibitor IInhibitor0.642
P-glycoprotein inhibitor IIInhibitor0.8387
Renal organic cation transporterNon-inhibitor0.6719
CYP450 2C9 substrateNon-substrate0.7897
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateSubstrate0.6032
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorInhibitor0.8932
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.9292
Ames testAMES toxic0.649
CarcinogenicityNon-carcinogens0.7244
BiodegradationNot ready biodegradable1.0
Rat acute toxicity1.7821 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9805
hERG inhibition (predictor II)Inhibitor0.5826
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
Packagers
Dosage formsNot Available
Prices
Unit descriptionCostUnit
Clofazimine powder187.2USD g
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point210-212 °CPhysProp
water solubility0.225 mg/L (virtually insoluble)Not Available
logP7.66QUIGLEY,JM ET AL. (1990)
pKa8.51QUIGLEY,JM ET AL. (1990)
Predicted Properties
PropertyValueSource
Water Solubility0.00151 mg/mLALOGPS
logP7.39ALOGPS
logP7.3ChemAxon
logS-5.5ALOGPS
pKa (Strongest Acidic)16.15ChemAxon
pKa (Strongest Basic)9.29ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area39.99 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity142.55 m3·mol-1ChemAxon
Polarizability51.52 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General ReferencesNot Available
External Links
ATC CodesJ04BA01
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (161 KB)
MSDSDownload (73.5 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Geobacillus kaustophilus (strain HTA426)
Pharmacological action
yes
Actions
inhibitor
General Function:
Oxidoreductase activity
Specific Function:
Not Available
Gene Name:
Not Available
Uniprot ID:
Q5L2G3
Molecular Weight:
39136.585 Da
References
  1. Cholo MC, Boshoff HI, Steel HC, Cockeran R, Matlola NM, Downing KJ, Mizrahi V, Anderson R: Effects of clofazimine on potassium uptake by a Trk-deletion mutant of Mycobacterium tuberculosis. J Antimicrob Chemother. 2006 Jan;57(1):79-84. Epub 2005 Nov 12. [PubMed:16286358 ]
2. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
yes
Actions
intercalation
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da
References
  1. Arbiser JL, Moschella SL: Clofazimine: a review of its medical uses and mechanisms of action. J Am Acad Dermatol. 1995 Feb;32(2 Pt 1):241-7. [PubMed:7829710 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular Weight:
141477.255 Da
References
  1. Wang EJ, Casciano CN, Clement RP, Johnson WW: Active transport of fluorescent P-glycoprotein substrates: evaluation as markers and interaction with inhibitors. Biochem Biophys Res Commun. 2001 Nov 30;289(2):580-5. [PubMed:11716514 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Transporter activity
Specific Function:
Involved in the ATP-dependent secretion of bile salts into the canaliculus of hepatocytes.
Gene Name:
ABCB11
Uniprot ID:
O95342
Molecular Weight:
146405.83 Da
References
  1. Wang EJ, Casciano CN, Clement RP, Johnson WW: Fluorescent substrates of sister-P-glycoprotein (BSEP) evaluated as markers of active transport and inhibition: evidence for contingent unequal binding sites. Pharm Res. 2003 Apr;20(4):537-44. [PubMed:12739759 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
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 xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Transporter activity
Specific Function:
Involved in the ATP-dependent secretion of bile salts into the canaliculus of hepatocytes.
Gene Name:
ABCB11
Uniprot ID:
O95342
Molecular Weight:
146405.83 Da
References
  1. Wang EJ, Casciano CN, Clement RP, Johnson WW: Fluorescent substrates of sister-P-glycoprotein (BSEP) evaluated as markers of active transport and inhibition: evidence for contingent unequal binding sites. Pharm Res. 2003 Apr;20(4):537-44. [PubMed:12739759 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular Weight:
141477.255 Da
References
  1. Wang EJ, Casciano CN, Clement RP, Johnson WW: Active transport of fluorescent P-glycoprotein substrates: evaluation as markers and interaction with inhibitors. Biochem Biophys Res Commun. 2001 Nov 30;289(2):580-5. [PubMed:11716514 ]
Comments
comments powered by Disqus
Drug created on June 13, 2005 07:24 / Updated on October 23, 2013 22:25