N-hydroxylation of 4,4?-diaminodiphenylsulphone (Dapsone) by liver microsomes, and in dogs and humans

Uehleke, H.; Tabarelli, Sonja

doi:10.1007/bf00501863

Cited by 40 publications

(17 citation statements)

References 33 publications

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“…Enterohepatic circulation occurs (Neuvonen et al, 1980) and the drug is extensively bound to serum proteins (Ahmad & Rogers, 1980a). The major metabolic pathways of DDS are Nacetylation, N-hydroxylation and conjugation reactions (Gelber et al, 1971;Uehleke & Tabarelli, 1973). Deacetylation of acetylated DDS also occurs (Gelber et al, 1971).…”

Section: Introduction Methodsmentioning

confidence: 99%

The pharmacokinetics of dapsone after oral administration to healthy volunteers.

Pieters¹,

Zuidema²

1986

Brit J Clinical Pharma

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After oral administration of 100 mg dapsone (DDS) to 25 healthy volunteers peak serum DDS concentrations between 1.10 and 2.33 mg I-1 were reached within 0.5 to 4 h. AUCs varied from 20.3 to 75.4 mg I -1 h, while the elimination half-lives ranged from 11.5 to 29.2 h. The apparent volumes of distribution were 0.84 to 1.26 1 kg-l body weight, assuming complete bioavailability. Statistically significant differences in peak drug concentration, peak time and AUC existed between males and females. Absorption and elimination of DDS appeared to be faster than reported in other studies, suggesting differences in DDS kinetics between healthy volunteers and patients.

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Section: Introduction Methodsmentioning

confidence: 99%

The pharmacokinetics of dapsone after oral administration to healthy volunteers.

Pieters¹,

Zuidema²

1986

Brit J Clinical Pharma

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“…Co-incubation of ketoconazole (100 FLM) with dapsone (1-100 FLM) and a metabolizing system in compartment A led to a decrease in methae- involving N-hydroxylation mediated by cytochrome P-450, may account for 30-50% of the dose (Israili et al, 1973;Uehleke & Tabarelli, 1973). The products of N-hydroxylation, dapsonehydroxylamine (DDS-NOH) and the monoacetyl derivative (MADDS-NOH) have been implicated as the metabolites responsible for the haematological disorders observed with dapsone therapy (Glader & Conrad, 1973;Grossman & Jollow, 1988).…”

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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“…Therefore, an important fraction of the dose is undoubtedly transformed and excreted into both the urine and bile as compounds that do not yield DDS on strong acid hydrolysis. It may be that the activity of some alternative pathways of metabolism and elimination of DDS, e.g., the formation and excretion of N-hydroxy (8,21) or ring-hydroxylated derivatives of DDS, differs greatly between the dog and man.…”

Section: Resultsmentioning

confidence: 99%

Renal and Biliary Disposition of Dapsone in the Dog

Biggs¹,

Uher²,

Levy

et al. 1975

Antimicrob Agents Chemother

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Dapsone (4,4'-diaminodiphenylsulfone [DDS]) was administered intravenously to anesthetized dogs; urine was collected, heparinized venous blood was obtained, and bile was collected from some of the dogs. A constant infusion of inulin was maintained, and isosmotic or hypoosmotic fluids were administered. Dogs were studied under conditions of standardized, increased or decreased urine flow, and before and after plasmapheresis. Plasma, urine, and bile samples were analyzed for DDS and DDS conjugates; the degree of binding of DDS by plasma proteins was also determined. The renal clearances of inulin and DDS were calculated. No monoacetyldapsone (MADDS) was detected in the plasma, and only negligible quantities were found in the urine. Small quantities of DDS and DDS conjugates were detected in the bile in 4 h following the dose. Between 10 and 30% of the administered drug could be identified as DDS plus DDS conjugates in the urine in 8 h after the dose. Renal clearance of unbound DDS was proportional to the urine flow rate, and the clearance ratio of DDS to inulin approached the same maximal value as that for urea. Although the rate of urinary excretion of DDS conjugates was the same in the dog as in man, the rates of excretion of DDS and of DDS plus DDS conjugates were greater in the dog than in man, suggesting that the acetylation of DDS to MADDS by man but not by the dog and the greater degree of plasma protein binding of DDS and MADDS by man account for the longer half-time of disappearance of DDS in man compared to that in the dog.In recent years, the disposition in man of dapsone (4,4'-diaminodiphenylsulfone, DDS), the drug most widely used in the treatment of leprosy patients (19), has been the subject of intensive investigation. The drug is acetylated polymorphically, its half-time of disappearance (t½) from the plasma is quite long, it is extensively metabolized, and both DDS and its acetylated metabolite (4-amino-4'-acetamidodiphenylsulfone, MADDS) are strongly bound by plasma proteins. MADDS represented 52% of the total of plasma DDS plus MADDS among nine rapid acetylators of isoniazid and sulfamethazine, whereas the corresponding value for 10 slow acetylators of these drugs was 17% (4). (4). DDS was found to be 70 to 81% and MADDS 97 to 100% bound by the plasma proteins of four rapid and six slow acetylators of DDS, and the degree of binding did not appear to be related to the acetylator phenotype (2). Finally, a study of the binding of DDS and MADDS to human serum albumin (18) showed the binding constant of MADDS to be quite large (2.35 x 105 liters/ mol), about 10 times larger than that of DDS. Another study reported MADDS to be 20 to 25 times more tightly bound than was DDS (5).A survey of other mammalian species demonstrated that, whereas DDS is extensively bound by the plasma proteins of all species studied (1),

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N-hydroxylation of 4,4?-diaminodiphenylsulphone (Dapsone) by liver microsomes, and in dogs and humans

Cited by 40 publications

References 33 publications

The pharmacokinetics of dapsone after oral administration to healthy volunteers.

The pharmacokinetics of dapsone after oral administration to healthy volunteers.

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

Renal and Biliary Disposition of Dapsone in the Dog

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