Identification

Name
Clofazimine
Accession Number
DB00845  (APRD00278)
Type
Small Molecule
Groups
Approved, 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
  • Riminophenazine
External IDs
B 663 / G 30320 / G-30320 / NSC 141046 / NSC-141046
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
LampreneCapsule, gelatin coated50 mg/1OralNovartis1986-12-152009-12-15Us
International/Other Brands
Clofozine (AstraZeneca) / Hansepran (Abbott) / Lamcoin (Pond's Chemical) / Lampren (Novartis) / Lamprène (Novartis) / Lamprene (Novartis)
Categories
UNII
D959AE5USF
CAS number
2030-63-9
Weight
Average: 473.396
Monoisotopic: 472.122152138
Chemical Formula
C27H22Cl2N4
InChI Key
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

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.

TargetActionsOrganism
ADNA
intercalation
Human
AUncharacterized oxidoreductase CzcO-like
inhibitor
Geobacillus kaustophilus (strain HTA426)
UBile salt export pumpNot AvailableHuman
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
  • Mycobacterium leprae
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of bleeding can be increased when Clofazimine is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Clofazimine is combined with (S)-Warfarin.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Clofazimine.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Clofazimine.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Clofazimine.
6-Deoxyerythronolide BThe metabolism of Clofazimine can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Clofazimine.
9-aminocamptothecinThe metabolism of 9-aminocamptothecin can be decreased when combined with Clofazimine.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Clofazimine.
AbirateroneThe metabolism of Abiraterone can be decreased when combined with Clofazimine.
Food Interactions
Not Available

References

General References
Not Available
External Links
KEGG Drug
D00278
KEGG Compound
C06915
PubChem Compound
2794
PubChem Substance
46508174
ChemSpider
2692
BindingDB
50378783
ChEBI
3749
ChEMBL
CHEMBL1292
Therapeutic Targets Database
DAP000789
PharmGKB
PA164748759
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Clofazimine
ATC Codes
J04BA01 — Clofazimine
FDA label
Download (161 KB)
MSDS
Download (73.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Infection, Mycobacterium Avium-Intracellulare1
2CompletedTreatmentPulmonary Tuberculosis (TB)1
2RecruitingTreatmentCryptosporidiosis infection1
2RecruitingTreatmentMycobacterium avium complex infection1
2, 3Not Yet RecruitingTreatmentPulmonary Tuberculosis (TB)1
2, 3RecruitingTreatmentExtensively Drug Resistant Tuberculosis / Pulmonary Tuberculosis (TB) / Tuberculosis, Multidrug Resistant1
3CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Infection, Mycobacterium Avium-Intracellulare1
3RecruitingTreatmentMulti-Drug Resistant Tuberculosis1
3RecruitingTreatmentTuberculosis, Multidrug Resistant1
4CompletedPreventionBorderline Lepromatous Leprosy / Leprosy, Lepromatous1
4Unknown StatusTreatmentCrohn's Disease (CD)1
Not AvailableCompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Infection, Mycobacterium Avium-Intracellulare1
Not AvailableCompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Mycobacterium Avium-intracellular Infection1
Not AvailableCompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Tuberculosis Infection1
Not AvailableRecruitingNot AvailableTuberculosis Infection1

Pharmacoeconomics

Manufacturers
  • Novartis pharmaceuticals corp
Packagers
  • Ciba Geigy Ltd.
  • Novartis AG
  • Physicians Total Care Inc.
  • Professional Co.
  • R.P. Scherer GmbH and Co. KG
Dosage forms
FormRouteStrength
Capsule, gelatin coatedOral50 mg/1
Prices
Unit descriptionCostUnit
Clofazimine powder187.2USD g
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)210-212 °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 FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-00fr-0000900000-e6674066d4ff0d54220f

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazanaphthalenes
Sub Class
Benzodiazines
Direct Parent
Phenazines and derivatives
Alternative Parents
Aniline and substituted anilines / Chlorobenzenes / Pyrazines / Aryl chlorides / Secondary ketimines / Heteroaromatic compounds / Secondary amines / Azacyclic compounds / Organopnictogen compounds / Organochlorides
show 1 more
Substituents
Phenazine / Aniline or substituted anilines / Chlorobenzene / Halobenzene / Aryl chloride / Aryl halide / Monocyclic benzene moiety / Benzenoid / Pyrazine / Heteroaromatic compound
show 11 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
phenazines, monochlorobenzenes (CHEBI:3749)

Targets

1. 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
Geobacillus kaustophilus (strain HTA426)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Oxidoreductase activity
Specific Function
Not Available
Gene Name
Not Available
Uniprot ID
Q5L2G3
Uniprot Name
Uncharacterized oxidoreductase CzcO-like
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]
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
Uniprot Name
Bile salt export pump
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
Substrate
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
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

Details
1. Bile salt export pump
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
Uniprot Name
Bile salt export pump
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
Uniprot Name
Multidrug resistance protein 1
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]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 04:51