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Clofazimine


ACCESSION NB: DB00845 (APRD00278)


TYPE: small molecule


GROUP: 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)

VOLUME OF DISTRIBUTION: Not Available

CATEGORIES:
Leprostatic Agents Antimycobacterials Dyes Coloring Agents

ABSORPTION: Absorption varies from 45 to 62% following oral administration in leprosy patients. Bioavailability is approximately 70%. Food increases bioavailability and rate of absorption.

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.

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.

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.

AFECTED ORGANISMS:
Mycobacteria