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Identification
Name Clofazimine
Accession Number DB00845 (APRD00278)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Chlofazimine
  • Clofazimina [INN-Spanish]
  • Clofaziminum [INN-Latin]
Brand names
  • Lampren
  • Lamprene
Brand name mixtures Not Available
Categories
  • Leprostatic Agents
  • Antimycobacterials
  • Dyes
  • Coloring Agents
CAS number 2030-63-9
Weight Average: 473.396
Monoisotopic: 472.122152138
Chemical Formula C27H22Cl2N4
InChI Key InChIKey=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+
Plain Text
IUPAC Name
N,5-bis(4-chlorophenyl)-3-[(propan-2-yl)imino]-3,5-dihydrophenazin-2-amine
SMILES
CC(C)\N=C1/C=C2N(C3=CC=C(Cl)C=C3)C3=C(C=CC=C3)N=C2C=C/1NC1=CC=C(Cl)C=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Benzene and Derivatives
  • Halobenzenes
  • Anilines
Substructures
  • Aliphatic and Aryl Amines
  • Benzene and Derivatives
  • Aryl Halides
  • Halobenzenes
  • Heterocyclic compounds
  • Aromatic compounds
  • Imines
  • Anilines
Pharmacology
Indication For the treatment of lepromatous leprosy, including dapsone-resistant lepromatous leprosy and lepromatous leprosy complicated by erythema nodosum leprosum.
Pharmacodynamics Clofazimine 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 action Appears 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.
Absorption Absorption varies from 45 to 62% following oral administration in leprosy patients. Bioavailability is approximately 70%. Food increases bioavailability and rate of absorption.
Volume of distribution Not Available
Protein binding Not 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.
Route of elimination Not Available
Half life 10 days following a single dose, 70 days after long-term, high-dose therapy.
Clearance Not Available
Toxicity Oral, 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
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
Packagers
Dosage forms
Form Route Strength
Capsule Oral
Prices
Unit description Cost Unit
Clofazimine powder 187.2 USD g
Patents Not Available
Properties
State solid
Melting point 210-212 oC
Experimental Properties
Property Value Source
water solubility 0.225 mg/L (virtually insoluble) PhysProp
logP 7 PhysProp
pKa 8.51 Various sources
Predicted Properties
Property Value Source
water solubility 1.51e-03 g/l ALOGPS
logP 7.39 ALOGPS
logP 7.30 ChemAxon Molconvert
logS -5.50 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 4 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 39.99 ChemAxon Molconvert
rotatable bond count 4 ChemAxon Molconvert
refractivity 142.55 ChemAxon Molconvert
polarizability 51.52 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00278 Link_out
KEGG Compound C06915 Link_out
PubChem Compound 2794 Link_out
PubChem Substance 46508174 Link_out
ChemSpider 2692 Link_out
ChEBI 3749 Link_out
ChEMBL 3749 Link_out
Therapeutic Targets Database DAP000789 Link_out
PharmGKB PA449044 Link_out
Drug Product Database 0 Link_out
RxList http://www.rxlist.com/cgi/generic3/clofazimine.htm Link_out
Drugs.com http://www.drugs.com/cons/clofazimine.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Clofazimine Link_out
ATC Codes
  • J04BA01
AHFS Codes Not Available
PDB Entries Not Available
FDA label show (161.4 KB)
MSDS show (73.5 KB)
Interactions
Drug Interactions
Drug Interaction
Food Interactions Not Available
Targets

1. DNA

Pharmacological action: yes
Actions: intercalation

DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.

Gene Sequence: FASTA

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. 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

2. Potassium transporter

Pharmacological action: yes
Actions: inhibitor
Organism class: bacterial
UniProt ID: Q5L2G3 Link_out
Gene: GK0582
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. 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
Enzymes

1. Cytochrome P450 3A4

Actions: substrate, inhibitor

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
Transporters

1. Bile salt export pump

Actions: inhibitor

Involved in the ATP-dependent secretion of bile salts into the canaliculus of hepatocytes

UniProt ID: O95342 Link_out
Gene: ABCB11 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

2. Multidrug resistance protein 1

Actions: inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:06

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.