Clofazimine

Drug Indication
1

For the treatment of lepromatous leprosy, including dapsone-resistant

lepromatous leprosy and lepromatous leprosy complicated by erythema
nodosum leprosum.from DrugBank [1]

Pharmacology and Biochemistry

1. Pharmacology
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.from DrugBank [1]
MeSH Pharmacological Classification
Leprostatic Agents
Substances that suppress Mycobacterium leprae, ameliorate the clinical
manifestations of leprosy, and/or reduce the incidence and severity of leprous
reactions.from MeSH [21]
Anti-Inflammatory Agents
Substances that reduce or suppress INFLAMMATION.from MeSH [22]
Established Pharmacologic Class [EPC]
Antimycobacterialfrom FDA Pharm Classes [6]
Absorption, Distribution and Excretion
Absorption
Absorption varies from 45 to 62% following oral administration in leprosy
patients. Bioavailability is approximately 70%. Food increases bioavailability and
rate of absorption.from DrugBank [1]

 Metabolism/Metabolites
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.from DrugBank [1]
Biological Half-Life
10 days following a single dose, 70 days after long-term, high-dose
therapy.from DrugBank [1]
Mechanism of Action
1

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.from DrugBank [1]

1. Toxicological Information
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.

Rifampin
Solubility
Freely sol in methyl chloride, dimethyl sulfoxide; sol in tetrahydrofuran; slightly
sol in water (pH less than 6), acetone, carbon tetrachloride
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and
Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p.
1474
Therapeutic Uses
Antibiotics, Antitubercular; Enzyme Inhibitors; Leprostatic Agents; Nucleic
Acid Synthesis Inhibitors
National Library of Medicine's Medical Subject Headings online file (MeSH,
1999)from HSDB [1]
Rifampin is used in combination with other agents in the treatment of leprosy
(Hansen's disease). /NOT included in US labeling/
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th
ed. Volume 1. Plus Updates. Content Reviewed by the United States
Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004., p. 2457from
HSDB [1]
Drug Warning
Rifampin has caused transient increases in serum concentrations of AST (SGOT),
ALT (SGPT), bilirubin, and alkaline phosphatase. Asymptomatic jaundice which
subsided without discontinuance of the drug has occurred occasionally. However,
hepatitis and fatalities associated with jaundice have been reported in patients
with preexisting liver disease or in those who received other hepatotoxic agents
concomitantly with rifampin. Rarely, hepatitis or a shocklike syndrome with
hepatic involvement with abnormal liver function test results (thought to be
allergic in nature) have been reported.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus
Supplements)., p. 574
from HSDB [1]
Pregnancy risk category: C /RISK CANNOT BE RULED OUT. Adequate, well
controlled human studies are lacking, and animal studies have shown risk to the
fetus or are lacking as well. There is a chance of fetal harm if the drug is given
during pregnancy; but the potential benefits may outweigh the potential risk./

Thomson.Micromedex. Drug Information for the Health Care Professional. 24th

ed. Volume 1. Plus Updates. Content Reviewed by the United States
Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004., p. 2337
from HSDB [1]
The leukopenic and thrombocytopenic effects of rifampin may result in an
increased incidence of certain microbial infections, delayed healing, and gingival
bleeding. If leukopenia or thrombocytopenia occurs, dental work should be
deferred until blood counts have returned to normal. Patients should be
instructed in proper oral hygiene, including caution in use of regular
toothbrushes, dental floss, and toothpicks. Rifampin may cause a
hypersensitivity reaction of sore mouth or tongue.
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th
ed. Volume 1. Plus Updates. Content Reviewed by the United States
Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004., p. 2458 from
HSDB [1]
Administration of rifampin on an intermittent schedule (less than twice weekly)
and/or daily doses of 1200 mg or greater is associated with frequent side
effects ... A flulike syndrome with fever, chills, and myalgias develops in 20% of
patients so treated. The syndrome also may include eosinophilia, interstitial
nephritis, acute tubular necrosis, thrombocytopenia, hemolytic anemia, and
shock.
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The
Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill,
2001., p. 1279 from HSDB [1]
Headache, drowsiness, fatigue, ataxia, dizziness, inability to concentrate, mental
confusion, behavioral changes, visual disturbances, muscular weakness,
myopathy, fever, generalized numbness, and pains in muscles, joints, and
extremities have occurred, especially during the first few weeks of rifampin
therapy.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus
Supplements)., p. 573-4from HSDB [1]
Thrombocytopenia, leukopenia, purpura, hemolytic anemia, hemolysis,
hemoglobinuria, hematuria, and decreased hemoglobin concentrations have
occurred with rifampin
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus
Supplements)., p. 574
from HSDB [1]

Rifampin and its metabolites may impart a red-orange color to urine, feces,
sputum, sweat, and tears; patients should be informed of this possibility. Soft
contact lenses worn during rifampin therapy may become permanently stained.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus
Supplements)., p. 575
from HSDB [1]
Commercially available rifampin sterile powder for injection contains sodium
formaldehyde sulfoxylate, a sulfite that may cause serious allergic-type reactions
in certain susceptible individuals. The overall incidence of sulfite sensitivity in the
general population is probably low, but in susceptible individuals, exposure to
sulfites can result in acute bronchospasm or, less frequently, life-threatening
anaphylaxis. Rifampin sterile powder for injection containing sodium
formaldehyde sulfoxylate should be used with caution in atopic, nonasthmatic
individuals.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus
Supplements)., p. 575
from HSDB [1]
Most patients tolerate and accept rifampin well. Abdominal distress, aching pain
in muscles and joints and cramping in the legs occur occasionally, especially
during the 1st few week of treatment.
American Medical Association, Council on Drugs. AMA Drug Evaluations Annual
1994. Chicago, IL: American Medical Association, 1994., p. 1645
from HSDB [1]
A case of acute org brain syndrome was assoc with rifampin administration in
treatment of pulmonary tuberculosis in 60-yr-old male who was treated with
recommended dosage for 42 days.
PRATT TH; RIFAMPIN INDUCED ORG BRAIN SYNDROME; J AM MED ASSOC 241:
2421 (1979)
from HSDB [1]
When rifampin is administered to patients with impaired liver function, they
should be kept under close medical supervision; serum enzyme levels should be
monitored in alcoholics and those with pre-existing liver disease for at least the
first two or three months of treatment.
American Medical Association, Council on Drugs. AMA Drug Evaluations Annual
1994. Chicago, IL: American Medical Association, 1994., p. 1645
from HSDB [1]

Renal failure is a rare complication associated with the use of rifampin.

Intravascular hemolysis leading to acute renal failure following rifampin therapy
is extremely rare. Two patients with leprosy who developed hemolysis and acute
renal failure following rifampin are reported.
Gupta A, et al; J Lepr Other Mycobact Dis 60 (2): 185-8 (1992)
from HSDB [1]
Although safe use of the drugs during pregnancy has not been definitely
established, rifampin (combined with isoniazid and/or ethambutol) has been used
to treat clinical tuberculosis in pregnant women. There are no adequate and
controlled studies to date using rifampin in pregnant women, and the drug
should be used during pregnancy only when the potential benefits justify the
possible risks to the fetus.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus
Supplements)., p. 575
from HSDB [1]
Increased BUN and serum uric acid concentrations, light chain proteinuria,
hematuria, renal insufficiency, interstitial nephritis, acute tubular necrosis, and
acute renal failure have occured infrequently with rifampin. Rifampin has also
been associated with precipitation of adrenocortical insufficiency in a few
patients with compromised adrenal function, possibly resulting from increased
cortisol metabolism secondary to hepatic microsomal enzyme induction.
Menstrual disturbances have also been reported.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus
Supplements)., p. 574
from HSDB [1]
A case with acute respiratory distress syndrome (ARDS) caused by rifampicin
during therapy for pulmonary tuberculosis /was reported/. A high level of
eosinophil cationic protein in bronchoalveolar lavage fluid (BALF) was detected
as well as interleukin-8 and neutrophil elastase. Based on these results together
with the positive result of the drug lymphocyte-stimulating test, /it was/
concluded that rifampicin was the causative drug leading to ARDS. Corticosteroid
therapy resulted in clinical improvement and resolution of the pulmonary
infiltrates on the chest radiograph without the recurrence of pulmonary
tuberculosis.
Ashitani J et al; Respiration 70 (5): 541-3 (2003)
from HSDB [1]
Minimum/Potential Fatal Human Dose

 In humans, acute overdosage with rifampin doses up to 9-12 g in adults and

one or two 100 mg/kg doses in children 1-4 years of age have not been fatal;
however, fatalities in adults have been reported following ingestion of 14 to 60 g
doses of the drug.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus
Supplements)., p. 577
from HSDB [1]

Pharmacology and Biochemistry

1. Pharmacology
Rifampin 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. Rifampin 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.from DrugBank [27]
MeSH Pharmacological Classification
Antibiotics, Antitubercular
Substances obtained from various species of microorganisms that are, alone or in
combination with other agents, of use in treating various forms of tuberculosis;
most of these agents are merely bacteriostatic, induce resistance in the
organisms, and may be toxic.from MeSH [53]
Cytochrome P-450 CYP2B6 Inducers
Drugs and compounds that induce the synthesis of CYTOCHROME P-450
CYP2B6.from MeSH [54]
Cytochrome P-450 CYP2C19 Inducers
Drugs and compounds that induce the synthesis of CYTOCHROME P-450
CYP2C19.from MeSH [55]
Cytochrome P-450 CYP2C8 Inducers
Drugs and compounds that induce the synthesis of CYTOCHROME P-450
CYP2C8.from MeSH [56]
Cytochrome P-450 CYP2C9 Inducers

Drugs and compounds that induce the synthesis of CYTOCHROME P-450

CYP2C9.from MeSH [57]
Cytochrome P-450 CYP3A Inducers
Drugs and compounds that induce the synthesis of CYTOCHROME P-450
CYP3A.from MeSH [58]
Leprostatic Agents
Substances that suppress Mycobacterium leprae, ameliorate the clinical
manifestations of leprosy, and/or reduce the incidence and severity of leprous
reactions.from MeSH [59]
Nucleic Acid Synthesis Inhibitors
Compounds that inhibit cell production of DNA or RNA.from MeSH [60]
Absorption, Distribution and Excretion
Rifampin is distributed throughout the body and is present in effective
concentrations in many organs and body fluids, including the CSF. This is perhaps
best exemplified by the fact that the drug may impart an orange-red color to the
urine, feces, saliva, sputum, tears, and sweat ... .
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The
Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill,
2001., p. 1278
from HSDB [1]
Up to 30% of a dose of the drug is excreted in the urine and 60% to 65% in the
feces; less than half of this may be unaltered antibiotic.
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The
Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill,
2001., p. 1278
from HSDB [1]
The oral administration of rifampin produces peak concentrations in plasma in 2
to 4 hours; after ingestion of 600 mg this value is about 7 ug/mL, but there is
considerable variability
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The
Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill,
2001., p. 1278
from HSDB [1]
Following absorption from the gastrointestinal tract, rifampin is eliminated
rapidly in the bile, and an enterohepatic circulation ensues.

Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The
Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill,
2001., p. 1278
from HSDB [1]
Rifampin was rapidly absorbed with mean peak serum levels of 5.9 mug/mL &
5.5 mug/mL, 2 hr and 1 hr after administration on days 1 and 8. Total urinary
excretion was greater on day 8 than day 1, reflecting well known enzyme
inducing activity of this drug.
EMERSON AM ET AL; J ANTIMICROB CHEMOTHER 4: 523 (1978)
from HSDB [1]
In a single-dose study in healthy fasting males, the extent of absorption (as
measured by area under the plasma concentration-time curve) of isoniazid,
rifampin, or pyrazinamide in dosages of 250, 6O0, or 1500 mg, respectively, was
similar whether the drugs were administered individually as capsules (rifampin)
and tablets (isoniazid and pyrazinamide) or as a fixed combination containing
isoniazid 50 mg, rifampin 120 mg, and pyrazinamide 300 mg per tablet.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus
Supplements)., p. 578
from HSDB [1]
... A bioassay was developed and used to examine levels of rifampin in the
posterior tibial nerve and serum of 8 patients (ages 17-70 yr), 6 of whom had
inactive leprosy, who received an oral dose of 600 mg rifampin. Within 8 to 12 hr
after ingestion of rifampin, the drug was detected in concn ranging from 0.52 to
4.1 mcg/mL in serum and in concn ranging from 0.6 to 6.3 ng/mg in posterior
tibial nerve fiber tissue.[Guebre-Xabier M, et al; Antimicrob Agents Chemother
39: 1866-70 (1995)] Full text: PMC162843from HSDB [1]
The effects of time and method of admin of rifampin with respect to feeding were
evaluated in five mature horses. There was a significant (P less than or equal to
0.05) delay in time of maximum serum concn and an apparent but not significant
incr in oral absorption when rifampin was given as a top dressing on grain as
compared with admin in corn syrup 2 hr before or 2 hr after feeding. Although
there were no differences between admin before or after feeding, admin 2 hr
prior to feeding was selected as the method of choice for future experiments.
The effects of age on rifampin disposition were subsequently examined using this
method of admin in six, l wk old foals. Rifampin (10 mg/kg) was given at incr age
from 1 through 10 wk and the pharmacokinetic disposition parameters
compared. There were significant differences in the slope of the elimination
phase (beta) and area under the curve (AUC ) at 1 wk through 6 wk compared
with 10 wk or with values in the five mature horses.

Burrows GE, et al; J Vet Pharmacol Ther 15 (2): 124-32 (1992)

from HSDB [1]
Comparison of the transcutaneous absorption of rifaximin (L/105; I) and rifampin
(rifampicin; II) in rats is described. Rifaximin was practically not absorbed after
topical, cutaneous application. On the contrary, under the same exptl /situation/
II was well absorbed. Results indicate that I may be useful for topical applications
of skin infections.
Venturni AP, et al; Drugs Exp Clin Res 8 (4): 231-32 (1987)
from HSDB [1]
Rifampicin (rifampin; I) serum and urine levels, as well as serum bilirubin, were
followed during and after parenteral I admin to 11 adult patients. Patients were
admin doses of either 300, 450, or 600 mg diluted to 500 mL as a continuous iv
infusion over a period of 3 hr. Patients had normal liver and renal function. Also,
patients had not received I previously or any enzyme inducing drug or antibiotic
within the last 4 wk or 5 days respectively. Iv and oral serum levels were similar.
Incr doses gave incr peaks and areas under the curve, while half-life remained
practically unchanged. Serum bilirubin levels followed the same patterns as seen
with oral I. Urinary excretion incr with larger dosages from 10% to almost 20% of
an admin dose. A 600 mg dose of I administered by iv drip over a 3 hr period
exhibits an overall pharmacokinetic pattern similar to that seen following the
same oral dose.
Nitti V, et al; Chemotherapy 23 (1): 1-6 (1977)
from HSDB [1]
Absorption
Well absorbed from gastrointestinal tract.from DrugBank [27]
Route of Elimination
Less than 30% of the dose is excreted in the urine as rifampin or
metabolites.from DrugBank [27]
Metabolism/Metabolites
The effects of rifampicin ... and phenobarbital ... on the metabolic fate of
isoniazid ... and hydrazine ... were studied in rats. Male Wistar rats were fasted
and injected with rifampicin at 30 mg/kg ip for 6 days, or with phenobarbital at
50 mg/kg for 3 days as pretreatment. After pretreatment, the rats were injected
with isoniazid at 40 mg/kg ip. Twenty four hour urine samples were collected, and
urinary concentrations of hydrazine and acetylhydrazine ... were determined by
gas chromatography/mass spectrometry. The rats were /sacrificed/, livers were
immediately perfused in situ and homogenized, and hepatic distribution of
metabolites was determined. Separately, blood was sampled and plasma

hydrazine concn were determined at 0.5, 1, 2, 3, and 4 hr after a jugular injection

of 5 mg/kg hydrazine. Within 1 hr after injection of isoniazid, hydrazine and
acetylhydrazine were detected in the liver and plasma. The concn of hydrazine in
rifampicin or phenobarbital pretreated groups were significantly lower than those
in the control group; the concn of acetylhydrazine were not altered. Pretreatment
with rifampicin or phenobarbital resulted in a marked incr in the urinary
elimination of hydrazine. ...
Noda A, et al; Toxicol Lett 25 (3): 313-17 (1985)
from HSDB [1]
In guinea pigs, rabbits and humans, major metabolite of rifampicin in urine and
bile is 25-o-deacetyl rifampicin; in body fluids of dogs and rats an unidentified
metabolite has been detected.
The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A
Review of the Literature Published Between 1970 and 1971. London: The
Chemical Society, 1972., p. 237
from HSDB [1]
Rifampin is metabolized in the liver to a deacetylated derivative which also
possesses antibacterial activity.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus
Supplements)., p. 578
from HSDB [1]
Several fast growing Mycobacterium strains were found to inactivate rifampin.
Two inactivated compounds (RIP-Ma and RIP-Mb) produced by these organisms
were different from previously reported derivatives, i.e., phosphorylated or
glucosylated derivatives, of the antibiotic. The structures of RIP-Ma and RIP-Mb
were determined to be those of 3-formyl-23-[O-(alpha-D-ribofuranosyl)]rifamycin
SV and 23-[O-(alpha-D-ribofuranosyl)]rifampin, respectively. To our knowledge,
this is the first known example of ribosylation as mechanism of antibiotic
inactivation.[Dabbs ER, et al; Antimicrob Agents Chemother 39 (4): 1007-9
(1995)] Full text: PMC162673from HSDB [1]
Metabolism
Primarily hepatic, rapidly deacetylated.from DrugBank [27]
Biological Half-Life
The half-life of rifampin varies from 1.5 to 5 hours and is increased in the
presence of hepatic dysfunction; it may be decreased in patients receiving
isoniazid concurrently who are slow inactivators of this drug. The half-life of
rifampin is progressively shortened by about 40% during the first 14 days of

treatment, owing to induction of hepatic microsomal enzymes with acceleration

of deacetylation of the drug.
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The
Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill,
2001., p. 1278
from HSDB [1]
The plasma half-life of rifampin in children 6-58 months of age averages 2.9
hours following oral administration of a single 10 mg/kg dose of the drug. Plasma
half-life of the drug in children 3 months to 12.8 years of age following IV doses
of the drug was 1.04-3.81 hours during the first few days of therapy and
decreased to 1.17-3.19 hours after 5-14 days of therapy.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus
Supplements)., p. 538
Mechanism of Action
Although rifampin is most active during cell multiplication ... /it/ appears to have
some effect on resting cells. Electron microscopy has revealed changes in
cytoplasm and disappearance of ribosomes in tubercle bacilli exposed to
rifampin, indicating inhibition of DNA-dependent RNA polymerase.
American Medical Association, AMA Department of Drugs, AMA Drug Evaluations.
3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977., p. 808
from HSDB [1]
Rifampin inhibits DNA-dependent RNA polymerase of mycobacteria and other
microorganisms by forming a stable drug-enzyme complex, leading to
suppression of initiation of chain formation (but not chain elongation) in RNA
synthesis. More specifically, the beta subunit of this complex enzyme is the site
of action of the drug, although rifampin binds only to the holoenzyme. Nuclear
RNA polymerase from a variety of eukaryotic cells does not bind rifampin, and
RNA synthesis is correspondingly unaffected. While rifampin can inhibit RNA
synthesis in mammalian mitochondria, considerably higher concentrations of the
drug are required than for the inhibition of the bacterial enzyme.
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The
Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill,
2001., p. 1278
from HSDB [1]
High concentrations of rifamycin antibiotics also inhibit viral DNA-dependent RNA
polymerases and reverse transcriptases.

Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The
Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill,
2001., p. 1278
from HSDB [1]
Rifampin is bactericidal for both intracellular and extracellular microorganisms.
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The
Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill,
2001., p. 1278
from HSDB [1]
Rifampin acts via the inhibition of DNA-dependent RNA polymerase, leading to a
suppression of RNA synthesis and cell death.from DrugBank [27]

Dapson

Pharmacology and Biochemistry

1. Pharmacology
Dapsone is a sulfone with anti-inflammatory immunosuppressive properties
as well as antibacterial and antibiotic properties. Dapsone is the principal drug in
a multidrug regimen recommended by the World Health Organization for the
treatment of leprosy. As an anti-infective agent, it is also used for treating
malaria and, recently, for Pneumocystic carinii pneumonia in AIDS patients.
Dapsone is absorbed rapidly and nearly completely from the gastrointestinal
tract. Dapsone is distributed throughout total body water and is present in all
tissues. However, it tends to be retained in skin and muscle and especially in the
liver and kidney: traces of the drug are present in these organs up to 3 weeks
after therapy cessation.from DrugBank [2]
MeSH Pharmacological Classification
Folic Acid Antagonists
Inhibitors of the enzyme, dihydrofolate reductase (TETRAHYDROFOLATE
DEHYDROGENASE), which converts dihydrofolate (FH2) to tetrahydrofolate (FH4).
They are frequently used in cancer chemotherapy. (From AMA, Drug Evaluations
Annual, 1994, p2033)from MeSH [40]
Anti-Infective Agents
Substances that prevent infectious agents or organisms from spreading or kill
infectious agents in order to prevent the spread of infection.from MeSH [41]
Leprostatic Agents
Substances that suppress Mycobacterium leprae, ameliorate the clinical
manifestations of leprosy, and/or reduce the incidence and severity of leprous
reactions.from MeSH [42]
Antimalarials
Agents used in the treatment of malaria. They are usually classified on the basis
of their action against plasmodia at different stages in their life cycle in the
human. (From AMA, Drug Evaluations Annual, 1992, p1585)from MeSH [43]

Absorption, Distribution and Excretion

DAPSONE IS SLOWLY & NEARLY COMPLETELY ABSORBED FROM GI
TRACT. ... PEAK CONCN IN...PLASMA ARE REACHED IN 2 TO 8 HR AFTER ADMIN;
THE MEAN HALF-LIFE OF ELIMINATION RANGES IS ABOUT 20 TO 30 HRS.

Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman
and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGrawHill, 1996., p. 1170
from HSDB [1]
TWENTY-FOUR HR AFTER ORAL INGESTION OF 100 MG, PLASMA CONCN
RANGE FROM 0.4 TO 1.2 UG/ML, & DOSE OF 100 MG/DAY PRODUCES AVG OF 2
UG OF "FREE" DAPSONE/G OF BLOOD OR NONHEPATIC TISSUE. ABOUT 70% OF
DRUG IS BOUND TO PLASMA PROTEIN.
Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman
and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGrawHill, 1996., p. 1170
from HSDB [1]
...ABOUT 70 TO 80% OF DOSE OF DAPSONE IS...EXCRETED. .../IT/ IS PRESENT IN
URINE AS ACID-LABILE MONO-N-GLUCURONIDE & MONO-N-SULFAMATE IN
ADDN TO...UNIDENTIFIED METABOLITES.
Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman
and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGrawHill, 1996., p. 1170
from HSDB [1]
SULFONES...DISTRIBUTED THROUGHOUT TOTAL BODY WATER &...PRESENT IN
ALL TISSUES. THEY TEND TO BE RETAINED IN SKIN & MUSCLE & ESP IN LIVER
& KIDNEY; TRACES... PRESENT IN THESE ORGANS UP TO 3 WK AFTER THERAPY
IS STOPPED. SULFONES ARE RETAINED IN CIRCULATION FOR LONG TIME
BECAUSE OF INTESTINAL REABSORPTION FROM BILE... /SULFONES/
Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman
and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGrawHill, 1996., p. 1170
from HSDB [1]
AFTER ORAL & INTRAMAMMARY ADMIN, DAPSONE WAS RAPIDLY ABSORBED
& 80-90% OF DOSE WAS AVAIL FOR DISTRIBUTION & ELIMINATION. AFTER
INTRAMAMMARY ADMIN APPROX 80% OF DOSE WAS RECOVERED IN URINE
WITHIN 72 HR, BUT URINARY RECOVERY OF UNCHANGED DAPSONE WAS LESS
THAN 20% OF DOSE.
ZIV G ET AL; REFU VET 35(2) 41 (1978)
from HSDB [1]
DAPSONE WAS RAPIDLY DISTRIBUTED THROUGHOUT BODY AFTER IV ADMIN
WITH DISTRIBUTION VOL EQUIVALENT TO 76% BODY VOL, & MEAN T/2 OF
APPROX 5 HR. AUTORADIOGRAPHY SHOWED IT TO BE EVENLY DISTRIBUTED
THROUGHOUT NORMAL UDDER AFTER INTRAMAMMARY INFUSION BUT LESS
SO IN GLAND.
ZIV G ET AL; REFU VET 35(2) 41 (1978)
from HSDB [1]
MONOACETYL-DAPSONE APPEARED TO BE MAJOR CIRCULATING METAB IN
GOAT BUT DISAPPEARED QUICKLY FROM BODY. SEVERAL OTHER METAB
WERE DETECTED IN URINE LONG AFTER DAPSONE & MONOACETYL-DAPSONE
WERE NO LONGER DETECTABLE. DAPSONE WAS 80-90% BOUND BY SERUM
BUT ONLY 15% IN MILK.
ZIV G ET AL; REFU VET 35(2) 41 (1978)
from HSDB [1]

AN AVG CONCN OF 1.2 MUG/ML DDS WAS FOUND IN BLOOD OF MICE

RECEIVING DIETS CONTAINING 0-01%. LIVER CONCN WAS ABOUT 2 TIMES
THAT IN BLOOD. SPLEEN CONCN WAS SLIGHTLY HIGHER THAN BLOOD BUT
MUSCLES CONTAINED MUCH LESS. NERVE CONCN WAS ABOUT EQUAL TO
THAT OF BLOOD.
BALAKRISHNAN S ET AL; INDIAN J MED RES 65(2) 201 (1977)
from HSDB [1]
Dapsone is distributed into most body tissues. Dapsone is reportedly retained in skin, muscle,
kidneys, and liver; trace concentrations of the drug may be present in these tissues up to 3
weeks after discontinuance of dapsone therapy. Dapsone is also distributed into sweat, saliva,
sputum, and tears. The drug is also distributed into bile.
McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus
Supplements)., p. 684
from HSDB [1]
Absorption

Bioavailability is 70 to 80% following oral administration.from DrugBank [2]

Route of Elimination

Renalfrom DrugBank [2]

Metabolism/Metabolites
HUMAN SUBJECTS ACETYLATE.../DAPSONE/ POLYMORPHICALLY
&...READILY DEACETYLATE MAJOR METABOLITE, MONOACETYL-DAPSONE. ...
DAPSONE WAS NOT ACETYLATED IN DOGS, & AN EQUIMOLAR DOSE OF
MONOACETYL-DAPSONE WAS DEACETYLATED SLOWLY TO DAPSONE BY
SAME ANIMALS.
The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 4: A Review of
the Literature Published during 1974 and 1975. London: The Chemical Society, 1977., p. 139
from HSDB [1]
IN URINE OF TREATED RATS, MAIN METABOLITE OF DAPSONE WAS DAPSONE
N-SULFAMATE, WITH SIMILAR AMT OF MONOACETYL-DAPSONE, NACETYLDAPSONE N'-SULFAMATE & DAPSONE N-GLUCURONIDE AS WELL AS
UNCHANGED DAPSONE, WHEREAS PRINCIPAL BILIARY METAB WAS DAPSONE
N-GLUCURONIDE.
The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 4: A Review of
the Literature Published during 1974 and 1975. London: The Chemical Society, 1977., p. 139
from HSDB [1]
DAPSONE.../IS/ N-ACETYLATED WHEN INCUBATED WITH WHOLE HUMAN
BLOOD OR WITH LEUKOCYTE SUSPENSIONS. ... MAN EXHIBITS NO
POLYMORPHISM IN THE IN VITRO ACETYLATION OF DAPSONE BY BLOOD...
The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 4: A Review of
the Literature Published during 1974 and 1975. London: The Chemical Society, 1977., p. 340
from HSDB [1]
IN HUMAN SUBJECTS GIVEN DAPSONE...N-OXIDATION METABOLITES WERE
FOUND IN URINE IN SIGNIFICANT AMT. PRIMARY URINARY

METAB...MONOHYDROXYLAMINE, WAS ISOLATED & CHARACTERIZED AS

AZOXYDAPSONE. A NEW METAB, MONOHYDROXYLAMINE OF /THE
METABOLITE/ 4-ACETYLAMINO-4'-AMINODIPHENYLSULFONE, WAS ALSO
IDENTIFIED.
The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The
Chemical Society, 1975., p. 297
from HSDB [1]
FORMATION OF MONONITRODAPSONE USING RAT LIVER MICROSOMES HAS
BEEN REPORTED. IT IS POSSIBLE THAT THIS INTERMEDIATE IS FORMED BY
NON-ENZYMATIC OXIDATION OF HYDROXYLAMINE. CONVERSION OF
MONOHYDROXYLAMINE DAPSONE INTO MONONITRODAPSONE HAS BEEN
NOTICED IN VITRO...IN PRESENCE & IN ABSENCE OF MICROSOMAL PROTEIN.
The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The
Chemical Society, 1975., p. 467
from HSDB [1]
FORMATION OF METAB, MONOHYDROXYLAMINE DAPSONE WOULD ACCOUNT
FOR HEMOTOXIC EFFECTS OF HIGH DOSES OF DAPSONE. AT LOW
(THERAPEUTIC) DOSES IN MAN, N-HYDROXYLATED METAB CONSTITUTE
ABOUT 1/2 OF DOSE. IN CIRCULATING BLOOD, THESE METAB ARE VIRTUALLY
COMPLETELY CONJUGATED WITH GLUCURONIC ACID...PREVENTING
FERRIHEMOGLOBIN FORMATION.
The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The
Chemical Society, 1975., p. 467
from HSDB [1]
Dapsone is acetylated in the liver to monoacetyl and diacetyl derivatives. The major
metabolite of dapsone is monoacetyldapsone. The rate of acetylation of dapsone is genetically
determined and is subject to interindividual variation, although the rate is usually constant for
each individual. The drug also is hydroxylated in the liver to hydroxylamine dapsone (NOHDDS). NOH-DDS appears to be responsible for methemoglobinemia and hemolysis induced
by the drug.
McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus
Supplements)., p. 684
from HSDB [1]
Metabolism

Hepatic, mostly CYP2E1-mediated.from DrugBank [2]

Biological Half-Life
There are large interindividual variations in the plasma half-life of dapsone. The plasma
half-life of dapsone may range from 10-83 hours and averages 20-30 hours.
McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus
Supplements)., p. 684
from HSDB [1]
28 hours (range 10-50 hours)from DrugBank [2]

Mechanism of Action

1.
...MECHANISM OF ACTION SIMILAR TO...SULFANILAMIDE...
SULFONAMIDES COMPETE WITH P-AMINOBENZOIC ACID & PREVENT ITS
NORMAL CELLULAR UTILIZATION, PARTICULARLY ITS INCORPORATION
INTO FOLIC ACID (PTEROYLGLUTAMIC ACID, PGA). ...SENSITIVE
ORGANISMS ARE PRIMARILY THOSE WHICH BECOME ABLE TO SYNTH
THEIR OWN FOLIC ACID. /SULFONAMIDES/
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed.
Easton, Pennsylvania: Mack Publishing Co., 1975., p. 1150
from HSDB [1]
1-30 UG/ML DAPSONE INTERFERED WITH MYELOPEROXIDASE-H2O2HALIDE-MEDIATED CYTOTOXIC SYSTEM IN POLYMORPHONUCLEAR
LEUKOCYTES. KINETIC STUDIES REVEALED COMPETITIVE INHIBITION
OF MYELOPEROXIDASE. ITS ACTION IN DERMATITIS HERPETIFORMIS
MAY BE EXPLAINED BY EFFECT ON THIS SYSTEM.
STENDAHL O ET AL; J CLIN INVEST 62(1) 214 (1978)
from HSDB [1]
IN STATIONARY BROTH CULTURES DAPSONE HAD MIN INHIBITORY
CONCN OF 0.3-0.5 UG/ML & WAS BACTERICIDAL AT 1.0 UG/ML; DRUG
ACTION WAS ANTAGONIZED BY 4-AMINOBENZOIC ACID (PABA) IN MOL
RATIO OF 2:1 (PABA:DAPSONE).
PANITCH ML ET AL; LEPR REV 49(2) 131 (1978)
from HSDB [1]
THE MECHANISM OF ACTION OF DAPSONE ON THE MULTIPLICATION OF
MYCOBACTERIUM LEPRAE IS DESCRIBED.
LEVY L ET AL; LEPR REV 48 (4) 237 (1977)
from HSDB [1]
Dapsone acts against bacteria and protozoa in the same way as sulphonamides, that is
by inhibiting the synthesis of dihydrofolic acid through competition with para-aminobenzoate for the active site of dihydropteroate synthetase. The anti-inflammatory
action of the drug is unrelated to its antibacterial action and is still not fully
understood.from DrugBank [2]