Dapsone excretion

Goodwin CS, SpareU G. Inhibition of dapsone excretion by probenecid. Lancet 1969 2(7626) 884—5. 

The occurence of drug interactions involving clofazimine have also been investigated. Most of the studies show that clofazimine does not exert any effect on dapsone excretion in leprosy patients (Balakrishnan and Seshadri, 1981 Zuidema et al., 1986). Clofazimine has been shown to significantly reduce the absorption of simultaneously administered rifampicin, resulting in delayed time to reach peak serum concentration and increased t j. No significant changes were seen in Cmax or AUC (Mehta et al., 1986). 

Sulfones, such as dapsone and sulfoxone (Diasone), are well absorbed orally and are widely distributed throughout body fluids and tissues. Peak concentrations of dapsone are reached within 1 to 3 hours of oral administration and have a half-life of 21 to 44 hours about 50% of administered dapsone is bound to serum proteins. The sulfones tend to remain in the skin, muscle, kidney, and liver up to 3 weeks after therapy is stopped. The concentration in inflamed skin is 10 to 15 times higher than that found in normal skin. The sulfones are retained in the circulation for a long time (12-35 days) because of hepatobiliary drug recirculation. The sulfones are acetylated in the liver, and 70 to 80% of drug is excreted in the urine as metabolites. 

In 28 patients with lepromatous leprosy, clofazimine did not influence the urinary excretion of dapsone, except in one case (46). 

When rifampicin was given, dapsone blood concentrations were lowered and urinary excretion was increased during the first 2 days however, blood concentrations remained in the therapeutic range (47). 

Edstein MD, Veenendaal JR, Newman K, Hyslop R. Excretion of chloroquine, dapsone and pyrimethamine in human milk. Br J Clin Pharmacol 1986 22(6) 733-5. 

Grabosz JA, Wheate HW. Effect of clofazimine on the urinary excretion of DDS (dapsone). Int J Lepr Other Mycobact Dis 1975 43(l) 61-2. 

Zidovudine is rapidly absorbed from the G1 tract with peak serum concentrations occurring within 30 to 90 minutes. It binds to plasma proteins to the extent of 35 to 40%. Zidovudine is rapidly metabolized in the liver to the inactive 3 -azido-3 -deoxy-5 -0-beta-D-glucopyranuronosylthymi-dine (GAZT), which has an apparent elimination half-life of 1 hour. Zidovudine undergoes glomerular filtration and active tubular secretion. Coadministration of zidovudine with agents such as dapsone, pentamidine, amphotericin B, flucytosine, vincristine, vinblastine, adriamycin, and interferon with potential to cause nephrotoxicity or cytotoxicity to hematopoietic elements, enhance its risk of adverse effects. Probenecid will inhibit the renal excretion of zidovudine. 

Dapsone is absorbed rapidly and nearly completely from the GI tract. Di-substituted sulfones (e.%., sulfoxone) are absorbed incompletely when administered orally and largely excreted in the feces. Peak concentrations of dapsone in plasma are reached within 2-8 hours after administration the mean t j is -20-30 hours. About 70% of the drug is bound to plasma protein. 

Approximately 70—80% of a dose of dapsone is excreted in the urine as an acid-labile mono-H-glucuronide and mono-N-sulfamate. 

Classification and pharmacokinetics The antifolate group includes pyrimethamine, proguanil, sulfadoxine, and dapsone. All of these drugs are absorbed orally and are excreted in the urine, partly in unchanged form. Proguanil has a shorter half-life (12-16 hours) than other drugs in this subclass (half-life > 100 hours). 

Probenecid inhibits renal tubular reabsorption of water and by this meehanism enhanees the urinary excretion of uric acid. This lowers the level of urate in the serum. It thus serves as a potent uricosuric agent in the treatment of gout. Probenecid also blocks the renal tubular seeretion of penicillins and cephalosporins. It is, therefore, used as an adjuvant therapy with penicillin V or G, ampicillin, cloxacillin, oxacillin, methicillin and naficillin to increase and prolong their plasma levels. Besides it also enhances the plasma levels of anti-inflammatory agents like naproxen and indomethacin, and a host of medicinal compounds such as sulphonamides, sulphonylureas, dapsone, etc. 

A study in patients taking elofazimine and dapsone and 4 other studies in patients also taking isoniazid or rifampiein suggest that clofazimine does not affeet the pharmaeokineties of dapsone. " However, one earlier study found that elofazimine transiently inereased the renal excretion of dapsone in 9 of 17 patients with leprosy who had recently discontinued dapsone. 

Twelve patients with quiescent tuberculoid leprosy were given dapsone 300 mg with probenecid 500 mg, and 5 hours later another 300-mg dose of dapsone. At 4 hours, the dapsone serum levels were raised about 50%. The urinary excretion of dapsone and its metabolites were reduced. ... 

Not fully examined. It seems probable that the probenecid inhibits the renal excretion of dapsone by the kidney. 

Rifampicin increases the urinary excretion of dapsone, lowers its serum ieveis and increases the risk of toxicity (methaemoglobinaemia). Simiiariy, rifabutin increases the clearance of dapsone, and may also increase its toxicity. 

An example of sequential blocking is the use of a sulfadiazine with pyrimethamine 9.31) in toxoplasmosis, a protozoal disease (Wettingfeld, Rowe and Eyles, 1956). In this sequence, the sulfonamide blocks the incorporation of / -aminobenzoic acid into dihydrofolic acid, and the pyrimethamine prevents the reduction of this pteridine to tetrahydrofolic acid (Sections 9.3.2 and 9.3.3). In malaria, as early as 1959, Hurly made the observation that pyrimethamine and sulfadiazine potentiated one another to such a degree that the combination could actually cure Pl.falciparum infections. Thus, less than 0.1 m.e.d. (minimal effective dose) of pyrimethamine and 0.25 m.e.d. of sulfadiazine were, together, as effective as 1.0 m.e.d. of either drug separately. In current tropical medicine, Maloprim , a combination of pyrimethamine and dapsone 9.17) (the latter chosen because of its slow rate of excretion which matches that of pyrimethamine), forms an excellent replacement for chloroquine in cases of Pl.falciparum... 

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