bacteriostatic; folate synthesis

Once 100 μg of protein has been added to cell lysates, dapsone is tested using the DHPS activity assay. In the DHPS activity assay, Dapsone has an IC50 of 3.0 μg/ml for E. Coli C600; however, at 256 μg/ml, Dapsone does not inhibit the growth of E. Coli C600. IC50 and MIC values for Dapsone for the recombinant strain containing M. leprae folP1 (pML101) are 0.06 μg/ml and 1 μg/ml, respectively[2].

Dapsone (topical treatment; 50 mg/kg; twice daily; 30 days) causes lesions to be about 186 mm2 in size in BALB/c mice infected with L. major as opposed to 125 mm2 in control mice. Moreover, 9.6±8.5 µg of DAP/mg of skin was measured for the lesions treated with DAP cream. But compared to mice that were not given the cream, the amount of parasites discovered in the spleen was noticeably reduced in the mice that received the cream[3].

Absorption, Distribution and Excretion
Bioavailability is 70 to 80% following oral administration.
Renal
After oral administration, absorption is almost complete ... . CL increases 0.03 L/hour and Vd 0.7 L increases for each 1-kg increase in body weight above 62.3 kg. Dapsone undergoes N-acetylation by NAT2. N-oxidation to dapsone hydroxylamine is via CYP2E1, and to a lesser extent by CYP2C. Dapsone hydroxylamine enters red blood cells, leading to methemoglobin formation. Sulfones tend to be retained for up to 3 weeks in skin and muscle and especially in liver and kidney. Intestinal reabsorption of sulfones excreted in the bile contributes to long-term retention in the bloodstream; periodic interruption of treatment is advisable for this reason. Epithelial lining fluid to plasma ratio is between 0.76 and 2.91; CSF-to-plasma ration is 0.21-2.01.
Approximately 70-80% of a dose of dapsone is excreted in the urine as an acid-labile mono-N-glucuronide and mono-N-sulfamate.
Following oral administration, dapsone is rapidly and almost completely absorbed from the GI tract and peak serum concentrations of the drug are attained within 4-8 hours. ... The volume of distribution of dapsone is reportedly 1.5-2.5 L/kg in adults. 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. ... Dapsone crosses the placenta. Dapsone is distributed into milk. ... Dapsone is 50-90% bound to plasma proteins. The major metabolite of dapsone, monoacetyldapsone, is almost completely bound to plasms proteins.
Approximately 20% of each dose of dapsone is excreted in urine as unchanged drug, 70-85% is excreted in urine as water-soluble metabolites, and a small amount is excreted in feces. Dapsone is excreted in urine as an acid-labile mono-N-glucuronide and mono-N-sulfamate derivatives in addition to some unidentified metabolites.
For more Absorption, Distribution and Excretion (Complete) data for DAPSONE (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Hepatic, mostly CYP2E1-mediated.
Leukocyte colony forming unit cell proliferation of bone marrow was markedly suppressed by 0.1 mmol & 1.0 mmol 4'-amino-4'-hydroxylaminodiphenyl sulfone (dapsone metab) when cells were cultured for 10-14 days.
Dapsone is acetylated in the liver to monoacetyl and diacetyl derivatives. The major metabolite of dapsone is monoacetyldapsone (MADDS). 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 (NOH-DDS). NOH-DDS appears to be responsible for methemoglobinemia and hemolysis induced by the drug.
Dapsone has known human metabolites that include N-Hydroxydapsone and Monoacetyldapsone.
Dapsone is slowly and nearly completely absporbed from GI tract, and distributed throughout the body. It 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 (NOH-DDS). NOH-DDS appears to be responsible for methemoglobinemia and hemolysis induced by the drug. The metabolites are excreted moslty in the urine. Only minor amounts of dapsone are excreted in feces. (A617, A618).
Route of Elimination: Renal
Half Life: 28 hours (range 10-50 hours)

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Biological Half-Life
28 hours (range 10-50 hours)
The elimination half-life is 20-30 hours.
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.

Toxicity Summary
IDENTIFICATION AND USE: Dapsone is a white or creamy white crystalline powder. Dapsone is approved for use in dermatitis herpetiformis and leprosy. It is particularly useful in the treatment of linear immunoglobulin (IgA) dermatosis, bullous systemic lupus erythematosus, erythema elevatum diutinum, and subcorneal pustular dermatosis. The drug is used as an alternative for treatment of Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia (PCP) and prevention of P. jirovecii infections. Dapsone is designated an orphan drug by the US FDA for treatment and prevention of PCP. It is also effective in treatment of endogenous uveitis, chronic conjunctivitis, keratitis, and keratoconjunctivitis, all caused by a previously unreported pathogenic microorganism, Micromyces intracellularis, in human eye. Dapsone may also be used as an analytic reagent and a hardening agent in the curing of epoxy resins. HUMAN EXPOSURE AND TOXICITY: Methemoglobinemia is the principal and constant feature of dapsone poisoning. Clinical features may include headache, dizziness, agitation, restlessness, nausea, vomiting, abdominal pain, bluish-grey cyanosis, tachycardia, hyperventilation, stupor, convulsions, coma, jaundice, and intravascular hemolysis. Adverse hematologic effects are most severe in patients with a G-6-PD deficiency. The dapsone hypersensitivity syndrome, which is associated with a reported mortality of 9.9%, develops in about 0.5 to 3.6% of persons treated with the drug. Dapsone may induce acute pancreatitis. ANIMAL STUDIES: Dapsone was added to rat food in a 78-week study. Mesenchymal tumors of abdominal organs or peritoneal tissues occurred in low and high dose males only. Fibroma, fibrosarcoma or sarcoma of spleen or peritoneum occurred most commonly. When dapsone was added to the food of mice at 500 or 1000 ppm for 78 weeks, it was not carcinogenic to either sex. Intragastric administration of 100 mg/kg dapsone to rats for 104 weeks produced spleen sarcomas in male, and higher morbidity from C-cell thyroid carcinomas of both sexes. Tumors appeared after lifetime treatment with maximum tolerated doses. Nervous effects developed following its oral administration to sheep. Incoordination, blindness, recumbency, bloat, opisthotonus, groaning and involuntary movements of the legs were reported in goats treated with an intramammary preparation containing dapsone, chloramphenicol and hyaluronidase. Oral administration of dapsone did not result in a significant degree of immunotoxicity in mice.
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-amino-benzoate 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.

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Hepatotoxicity
Dapsone, like other sulfonamides, causes a characteristic idiosyncratic liver injury that has features of drug-allergy or hypersensitivity. The typical onset is sudden development of fever and rash followed by jaundice within a few days or weeks of starting the medication. Eosinophilia or lymphocytosis are also common. The presentation can resemble acute mononucleosis and is often referred to as "sulfone syndrome" which is a variant of the "drug rash with eosinophilia and systemic symptoms" (DRESS) syndrome. The pattern of injury is typically cholestatic or mixed and can be complicated and prolonged. In rare instances, dapsone induced liver injury has resulted in acute liver failure. However, most cases resolve rapidly, usually within 2 to 4 weeks of stopping dapsone, unless cholestasis is severe.
Likelihood score: A (well known cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Dapsone can be used during breastfeeding; however, hemolytic anemia might occur, especially in newborn infants and in those with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The time of greatest risk for hemolysis in fullterm newborns without G6PD deficiency might be as short as 8 days after birth. One source states that use of dapsone in the treatment of leprosy is advantageous because it kills the organisms in breastmilk. Monitor the infant for signs of hemolysis, especially in newborn or premature breastfed infants.
Topical dapsone gel used to treat acne has not been studied during breastfeeding. According to the manufacturer, topical dapsone gel results in a blood level of 1% that of a 100 mg oral dose. It is unlikely that the topical gel would affect the breastfed infant, but the manufacturer states that it should not be used during nursing. Until more data are available, an alternative topical agent might be preferred.
◉ Effects in Breastfed Infants
A case of mild hemolytic anemia occurred in a 41-day-old breastfed infant whose mother was taking dapsone 50 mg daily. The hemolysis was probably caused by dapsone in milk.
A woman with leprosy took dapsone, clofazimine and rifampin during pregnancy and breastfeeding. Her infant developed skin discoloration attributed to clofazimine which reversed 3 months after cessation of breastfeeding.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
70 to 90%

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Toxicity Data
LD50: 496 mg/kg (Oral, Mouse)

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Interactions
... When dapsone is co-administered with trimethoprim the resulting plasma concentrations for both drugs are higher than when either drug is taken alone. In a comparative trial of TMP/dapsone versus TMP-SMX, response rates of 93% and 90% were observed, respectively.
Because the drugs have similar adverse hematologic effects, concurrent use of a folic acid antagonist (e.g., pyrimethamine) and dapsone may result in an increased risk of these adverse effects. Agranulocytosis has developed during the second and third months of therapy in patients receiving concomitant treatment with weekly pyrimethamine and dapsone. If pyrimethamine is used concomitantly with dapsone, the patient should be monitored more frequently than usual for adverse hematologic effects. Because effects may be additive, dapsone should be used with caution in patients with G-6-PD deficiency receiving or exposed to other drugs or agents which are capable of inducing hemolysis in these individuals (e.g., nitrite, aniline, phenylhydrazine, naphthalene, niridazole, nitrofurantoin, primaquine).
Results of several studies indicate that concomitant clofazimine does not affect the pharmacokinetics of dapsone, although a transient increase in urinary excretion of dapsone reportedly occurred in a few patients receiving concomitant therapy with the drugs. In a study in lepromatous leprosy patients receiving dapsone (100 mg daily) and rifampin (600 mg daily), concomitant administration of clofazimine (100 mg daily) did not affect plasma dapsone concentrations or the plasma half-life or urinary elimination of dapsone. There is some evidence that dapsone may decrease or nullify some of the anti-inflammatory effects of clofazimine.
Failure of dapsone to prevent Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia (PCP) was reported in about 40% of patients with human immunodeficiency virus (HIV) infection who were receiving didanosine concomitantly. This failure rate was substantially higher than that reported in other studies in which dapsone was not administered with didanosine or that were observed when didanosine was used in patients receiving co-trimoxazole or aerosolized pentamidine for prevention of PCP. Although the possibility of a pharmacokinetic interaction was not evaluated in these patients, it was suggested that the buffers present in the didanosine preparation, which provides a pH of 7-8 to facilitate GI absorption of the antiretroviral agent, may interfere with GI absorption of dapsone.
For more Interactions (Complete) data for DAPSONE (9 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 1000 mg/kg
LD50 Rat ip 196 mg/kg
LD50 Mouse oral 375 mg/kg
LD50 Mouse ip 313 mg/kg
LD50 Mouse sc 329 mg/kg

[1]. Dapsone and sulfones in dermatology: overview and update. J Am Acad Dermatol

[2]. Interaction of Pneumocystis carinii dihydropteroate synthase with sulfonamides and diaminodiphenyl sulfone (dapsone).J Infect Dis. 1994 Feb;169(2):456-9.

[3]. Evaluation of Skin Permeation and Retention of Topical Dapsone in Murine Cutaneous Leishmaniasis Lesions.Pharmaceutics. 2019 Nov 13;11(11):607.

Therapeutic Uses
Anti-Infective Agents; Antimalarials; Folic Acid Antagonists; Leprostatic Agents
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Dapsone is included in the database.
Dapsone is administered as an oral agent. Dapsone is combined with chlorproguanil for the treatment of malaria. Dapsone is also used for P. jiroveci infection and prophylaxis, and for the prophylaxis for T. gondii ... The anti-inflammatory effects are the basis for therapy for pemphigoid, dermatitis herpetiformis, linear IgA bullous disease, relapsing chondritis, and ulcers caused by the brown recluse spider.
Dapsone is approved for use in dermatitis herpetiformis and leprosy. It is particularly useful in the treatment of linear immunoglobulin (IgA) dermatosis, bullous systemic lupus erythematosus, erythema elevatum diutinum, and subcorneal pustular dermatosis.
For more Therapeutic Uses (Complete) data for DAPSONE (14 total), please visit the HSDB record page.

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Drug Warnings
Peripheral neuropathy with motor loss has been reported rarely in patients receiving high dosage of dapsone (200-500 mg daily). ... Insomnia, headache, nervousness, vertigo, and psychosis have also been reported with dapsone.
Resistance to dapsone in P. falciparum, P. jiroveci, and M. leprae results primarily from mutations in genes encoding dihydropteroate synthase.
Hemolysis develops in almost every individual treated with 200-300 mg of dapsone per day. ... Methemoglobinemia is also common. A genetic deficiency in the NADH-dependent methemoglobin reductase can result in severe methemoglobinemia after administration of dapsone. Isolated instances of headache, nervousness, insomnia, blurred vision, paresthesias, reversible peripheral neuropathy (thought to be sue to axonal degeneration), drug fever, hematuria, pruritus, and a variety of skin rashes have been reported. An infectious mononucleosis-like syndrome, which may be fatal, occurs occasionally.
Glucose-6-phosphate dehydrogenase (G6PD) protects red cells against oxidative damage. However, G6PD deficiency is encountered in nearly half a billion people worldwide, the most common of 100 variants being G6PD-A-. Dapsone, an oxidant, causes severe hemolysis in patients with G6PD deficiency. Thus, G6PD deficiency testing should be performed prior to use of dapsone wherever possible.
For more Drug Warnings (Complete) data for DAPSONE (11 total), please visit the HSDB record page.

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Pharmacodynamics
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.

C12H12N2O2S

248.3009

248.061

C, 58.05; H, 4.87; N, 11.28; O, 12.89; S, 12.91

80-08-0

Dapsone-d8;557794-38-4;Dapsone-d4;1346602-12-7;Dapsone-13C12;1632119-29-9

2955

Crystals from 95% ethanol
White or creamy white crystalline powder

1.4±0.1 g/cm3

511.7±35.0 °C at 760 mmHg

175-177 °C(lit.)

263.2±25.9 °C

0.0±1.3 mmHg at 25°C

1.662

0.94

2

4

2

17

306

0

O=S(C1C=CC(N)=CC=1)(C1C=CC(N)=CC=1)=O

MQJKPEGWNLWLTK-UHFFFAOYSA-N

InChI=1S/C12H12N2O2S/c13-9-1-5-11(6-2-9)17(15,16)12-7-3-10(14)4-8-12/h1-8H,13-14H2

4-(4-aminophenyl)sulfonylaniline

Diaphenylsulfone; 4,4'-Sulfonyldianiline; 4,4'-Diaminodiphenyl sulfone; Sulfona; 4,4′-Diaminodiphenyl sulfone; DDS

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 49~250 mg/mL ( 197.34~1006.85 mM )
Ethanol : ~10 mg/mL

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.07 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (10.07 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (10.07 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (10.07 mM)

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 (Please use freshly prepared in vivo formulations for optimal results.)