Clinical Pharmacokinetics of Dapsone

Zuidema, J.; Hilbers-Modderman, E. S. M.; Merkus, F. W. H. M.

doi:10.2165/00003088-198611040-00003

Cited by 237 publications

(205 citation statements)

References 63 publications

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“…4K). The DDS dosage used in the C2C12 cells (20 μM) was optimized based on the observation that the long-term administration of DDS at standard doses (100 mg 20). Taken together, our results strongly suggest that the DDS effect is similar in worms and mammals.…”

mentioning

confidence: 66%

DDS, 4,4′-diaminodiphenylsulfone, extends organismic lifespan

Cho

Park

Keam

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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DDS, 4,4′-diaminodiphenylsulfone, is the most common drug prescribed to treat Hansen disease patients. In addition to its antibacterial activity, DDS has been reported to be involved in other cellular processes that occur in eukaryotic cells. Because DDS treatment significantly enhances the antioxidant activity in humans, we examined its effect on lifespan extension. Here we show that DDS extends organismic lifespan using Caenorhabditis elegans as a model system. DDS treatment caused a delay in aging and decreased the levels of a mitochondrial complex. The oxygen consumption rate was also significantly lowered. Consistent with these data, paraquat treatment evoked less reactive oxygen species in DDS-treated worms, and these worms were less sensitive to paraquat. Interestingly enough, all of the molecular events caused by DDS treatment were consistently reproduced in mice treated with DDS for 3 mo and in the C2C12 muscle cell line. Structural prediction identified pyruvate kinase (PK) as a protein target of DDS. Indeed, DDS bound and inhibited PK in vitro and inhibited it in vivo, and a PK mutation conferred extended lifespan of C. elegans. Supplement of pyruvate to the media protected C2C12 cells from apoptosis caused by paraquat. Our findings establish the significance of DDS in lowering reactive oxygen species generation and extending the lifespan, which renders the rationale to examining the possible effect of DDS on human lifespan extension.F irst synthesized a century ago, 4,4′-diaminodiphenylsulfone (DDS) is a drug still used to treat many skin diseases. Specifically, DDS is a principal drug in a multidrug regimen recommended by the World Health Organization for the treatment of leprosy (1-4). DDS acts as an antibiotic in a manner similar to sulphonamides by inhibiting bacterial synthesis of dihydrofolic acid through competition with para-aminobenzoic acid (PABA) for the active site of dihydropteroate synthetase (DHPS) (5). In addition to its antibacterial activity, DDS has been reported to be involved in other cellular processes that occur in eukaryotic cells, such as inflammation, migration, and apoptosis (6). However, there has been controversy over the issue of whether DDS acts as a pro-oxidant (especially when a higher dose of DDS is used rather than a standard dose) or antioxidant (7-9). Most studies on the pro-oxidant effects of DDS have been based on its use at high concentrations. For example, in human dermal fibroblasts, a high dose of DDS (1.5 mM) induced oxidative stress and glutathione depletion (10), but in rat livers, DDS administration at a dose of 30 mg/kg body weight resulted in oxidative stress (11). Therefore, the debate regarding the nature of DDS as a pro-oxidant or antioxidant appears to reflect the dosage effect. Another interesting observation is that Hansen disease patients in Korea, who usually have taken DDS for several decades, had a longer lifespan in spite of their socioeconomical disadvantages (12). This finding prompted us to examine whether and how DDS treatment extends an...

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mentioning

confidence: 66%

DDS, 4,4′-diaminodiphenylsulfone, extends organismic lifespan

Cho

Park

Keam

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Uetrecht et al (1988) have demonstrated that dapsone may be oxidized in vitro by activated polymorphonuclear leucocytes to 4-amino-4'-nitro-diphenylsulphone via the toxic hydroxylamine and nitroso intermediates, which might account for the cell-specific toxicity observed. However, the incidence of agranulocytosis due to dapsone administration is idiosyncratic and relatively rare (< 1 in 2000), whilst methaemoglobin formation and reduction in erythrocyte life-span is dose-dependent and occurs to some extent in all subjects who take the drug (Zuidema et al, 1986).…”

Section: Inhibition Of Methaemoglobin Formationmentioning

confidence: 99%

An investigation of the role of metabolism in dapsone‐induced methaemoglobinaemia using a two compartment in vitro test system.

Tingle

Coleman

Park

1990

Brit J Clinical Pharma

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1. We have utilized a two compartment system in which two teflon chambers are separated by a semi‐permeable membrane in order to investigate the role of metabolism in dapsone‐induced methaemoglobinaemia. Compartment A contained a drug metabolizing system (microsomes prepared from human liver +/‐ NADPH), whilst compartment B contained target cells (human red cells). 2. Incubation of dapsone (1‐ 100 microM) with human liver microsomes (2 mg protein) and NADPH (1 mM) in compartment A (final volume 500 microliters) led to a concentration‐ dependent increase in the methaemoglobinaemia (15.4‐18.9% at 100 microM) compared with control (2.3 +/‐ 0.4%) detected in the red cells within compartment B. In the absence of NADPH dapsone had no effect. 3. Of the putative dapsone metabolites investigated, only dapsone‐ hydroxylamine caused methaemoglobin formation in the absence of NADPH (40.6 +/‐ 6.3% with 100 microM). However, methaemoglobin was also detected when monoacetyl‐dapsone, 4‐amino‐4′‐nitro‐diphenylsulphone and 4‐aminoacetyl‐4′‐nitro‐diphenylsulphone were incubated with human liver microsomes in the presence of NADPH. 4 Dapsone‐dependent methaemoglobin formation was inhibited by addition of ketoconazole (1‐1000 microM) to compartment A, with IC50 values of 285 and 806 microM for the two liver microsomal samples studied. In contrast, methaemoglobin formation was not inhibited by cimetidine or a number of drugs pharmacologically‐ related to dapsone. The presence of glutathione or ascorbate (500 microM) did not alter the level of methaemoglobin observed.

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“…Phenotyping with this drug has been shown to give results comparable with those using the elimination half-life of isoniazid or the urinary excretion ratio of acetylsulphamethazine to sulphamethazine (Gelber et al, 1971;Hanson etal., 1981). The plasma acetylation ratio of monoacetyldapsone (MADDS) to DDS at 3 h after a single oral dose of 100 mg of DDS is commonly used for phenotyping (Reidenberg et al, 1975;Clark, 1985;Zuidema et al, 1986). However, the possibility of using non-invasive urinary measurements has not been investigated systematically.…”

Section: Introductionmentioning

confidence: 99%

N‐acetylation phenotyping with dapsone in a mainland Chinese population.

Horai

Zhou

Zhang

et al. 1988

Brit J Clinical Pharma

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1 The N-acetylation of dapsone (DDS) was studied in 108 unrelated Chinese subjects residing in the mainland of China. 2 The frequency of slow acetylators determined using the plasma monoacetyldapsone to DDS ratio (MADDS/DDS, slow acetylators < 0.30 and rapid acetylators > 0.35) at 3 h after an oral dose of DDS (100 mg) was 13.0% (14 of the 108 subjects) with a 95% confidence interval of 7.9 to 20.6%. 3 The mean plasma concentration of MADDS was about three times lower in the slow than in the rapid acetylators and there was a highly significant correlation (r, = 0.886, P < 0.001) between plasma MADDS concentration and acetylation ratio. 4 Urinary acetylation ratios (MADDS/DDS) and cumulative urinary excretion of MADDS were significantly (P < 0.001) lower in slow acetylators compared with rapid acetylators. In addition, there was a significant relationship (rs = 0.510 to 0.718, P < 0.001) between plasma and urinary acetylation ratios. However, the distribution of the urinary acetylation ratio was not bimodal. 5 The urinary acetylation ratio after an oral dose of DDS is not a discriminative index for determining acetylation phenotype.

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Clinical Pharmacokinetics of Dapsone

Cited by 237 publications

References 63 publications

DDS, 4,4′-diaminodiphenylsulfone, extends organismic lifespan

DDS, 4,4′-diaminodiphenylsulfone, extends organismic lifespan

An investigation of the role of metabolism in dapsone‐induced methaemoglobinaemia using a two compartment in vitro test system.

N‐acetylation phenotyping with dapsone in a mainland Chinese population.

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