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PubMed1994

Dapsone-induced hematologic toxicity: comparison of the methemoglobin-forming ability of hydroxylamine metabolites of dapsone in rat and human blood.

The relative methemoglobin (MetHgb) forming ability of two metabolites of dapsone, dapsone hydroxylamine (DDS-NOH) and monoacetyldapsone hydroxylamine (MADDS-NOH), were compared in rat and human whole blood. Concentration-response curves for the two metabolites were generated in vitro in whole blood. Data were fit to both the Emax and Sigmoid Emax models. The Emax values for MetHgb formation in rat blood for MADDS-NOH and DDS-NOH fitted to the Emax model were 83 (8) and 84 (2)%, while the EC50 values were 1087 (283) and 828 (104) microM, respectively (mean +/- SD). Neither these values nor those generated for the Sigmoid Emax model differed significantly between the two metabolites. Similarly, the Emax values in human blood for MADDS-NOH and DDS-NOH fitted to the Emax model were 79 (5) and 80 (2)%, while the EC50 values were 90 (17) and 95 (19) microM, respectively. These values also did not differ between the two metabolites using either pharmacodynamic model. MetHgb was produced at the same rate, reached similar peak concentrations, and exhibited the same rate of decline with both metabolites. The area under the MetHgb content versus time curve did not differ between the two metabolites. These data demonstrate that MADDS-NOH and DDS-NOH are equipotent and equally efficacious in their MetHgb-forming ability. Investigation of the disposition of these metabolites is necessary to assess their relative role in dapsone-induced toxicity in vivo.

Adult↗

PubMed1992

Dapsone-induced hemolytic anemia: effect of N-hydroxy dapsone on the sulfhydryl status and membrane proteins of rat erythrocytes.

Dapsone hydroxylamine (DDS-NOH), a known metabolite of dapsone, has recently been shown to be a direct-acting hemotoxin responsible in part for dapsone-induced hemolytic anemia in the rat. The effect of DDS-NOH on the morphology, sulfhydryl status, and membrane skeletal proteins of the rat red cell has been investigated. Exposure of rat red cells to a TC50 of DDS-NOH induced transformation of about 50% of the cells to an extreme echinocyte morphology. Reduced glutathione content of the cells was rapidly lost with concomitant increase in the formation of mixed disulfide between glutathione and the soluble protein of the cell. Oxidized glutathione content of the cells did not increase at any time during exposure to DDS-NOH. Examination of the skeletal membrane proteins by SDS-PAGE indicated that DDS-NOH caused the apparent loss of band 4.2, decrease in peaks 1, 2.1, and 3, and the appearance of new bands at about 16, 27, 40, and 54 kDa. Bands 4.1 and 7 appeared unchanged. Treatment of DDS-NOH altered proteins with dithiothreitol, reversed the protein changes, and indicated that the observed alterations were due to the formation of disulfide-linked adducts between hemoglobin and the various skeletal proteins as well as between hemoglobin monomers. The possible significance of the parallel changes in cell morphology and in membrane skeletal proteins for the premature splenic sequestration of the injured rat red cells is discussed.

Anemia, Hemolytic↗

PubMed1979

Determination of plasma concentrations of dapsone, monoacetyl dapsone and pyrimethamine in human subjects dosed with maloprim.

A high-performance liquid chromatographic method was developed to enable dapsone, monoacetyl dapsone and pyrimethamine to be measured simultaneously in plasma samples from volunteers in England and Malaysia who had been dosed with Maloprim. Mean half-lives of 25 and 80 h were calculated for dapsone and pyrimethamine, respectively, but there was wide individual variation. All subjects were found to be classifiable as "slow acetylators".

Adult↗

PubMedDate not supplied

Relapses in leprosy patients treated with rifampicin plus dapsone after varying periods of dapsone monotherapy.

Leprosy patients treated formerly with dapsone monotherapy followed by combined therapy with rifampicin plus dapsone were surveyed for relapse and rifampicin resistance. The relapse rate was significantly low for the 482 multibacillary (MB) patients receiving > 12 months combined therapy compared with the 49 MB cases receiving < 12 months of combined therapy. The relapse rate was related to the duration of dapsone monotherapy prior to combined therapy. The difference in relapse rate in 247 paucibacillary (PB) patients following > 12 months combined therapy was also of significance, compared with the 66 PB cases who had received < 12 months combined therapy. Five strains of M. leprae isolated from relapsed patients were sensitive to rifampicin by mouse foot-pad test and all relapsed patients responded favourably to fixed duration MDT regimen for MB cases.

Animals↗

PubMed1979

The pharmacokinetics of dapsone and acetylated dapsone in serum and saliva.

The concentrations of dapsone (DDS) and its acetylated derivatives (MADDS and DADDS) were determined in the serum and saliva after one oral dose of dapsone until 72 hr. The peak serum concentrations of DDS and MADDS were reached, on average, at 3.8--4.3 hr after the dosage. The amounts of DADDS were negligible. The elimination half-life of the first order kinetics was, on average, at 20--21 hr for both DDS and MADDS. The study group included 6 rapid acetylators and 4 slow acetylators with the mean ratios MADDS/DDS 1.0 and 0.19, respectively. No difference in the pharmacokinetics of DDS or MADDS could be seen between the rapid and slow acetylators. The protein-free fractions of DDS and MADDS were 50 and 41 per cent, respectively, of the total serum concentrations as measured at 8 and 32 hr after the dosage. The salivary concentration of DDS was, on average, 49 per cent of the total serum concentration during the whole study period. The salivary concentration of MADDS was 40 per cent, respectively. The elimination half-life of DDS and MADDS in saliva did not differ from that in serum. Between the salivary and serum protein-free concentrations a strict correlation existed (p less than 0.001). The salivary concentration of dapsone and its monoacetyl derivative reflect the protein-free, active drug in serum.

Acetylation↗

PubMed1996

The effect of acetylation and deacetylation on the disposition of dapsone and monoacetyl dapsone hydroxylamines in human erythrocytes in-vitro.

The fates of both dapsone and monoacetyl hydroxylamine have been studied in terms of acetylation and deacetylation within the human erythrocyte in-vitro. A comparison between the two metabolites showed equipotency in methaemoglobin generation at 15 min, although the monoacetyl derivative was the more rapid haemoglobin oxidizer. Within the erythrocytes, both dapsone and monoacetyl hydroxylamines were found to undergo acetylation, deacetylation and diacetylation. Of the inhibitors of acetylation studied, folate caused an increase in methaemoglobin formation associated with both metabolites, which led to a rise in both acetylated and non-acetylated amine formation. Amethopterin was associated with a rise in hydroxylamine mediated methaemoglobin formation which coincided with a fall in acetylated products. It is possible that the hydroxylamines undergo erythrocytic processes of acetylation and deacetylation before methaemoglobin-mediated reduction to their respective amines.

Acedapsone↗

PubMed2000

CYP2C8/9 mediate dapsone N-hydroxylation at clinical concentrations of dapsone.

Using selective cytochrome P450 (CYP) inhibitors and clinical concentrations (4 microM) of dapsone (DDS), we found a major contribution of CYP2C9 and little or no contribution (< or = 10%) of CYP3A4 and CYP2E1 to dapsone N-hydroxylation (DDS-NHY) in human liver microsomes. Sulfaphenazole (2.16 microM) and tolbutamide (500 microM), selective inhibitors of CYP2C9 (or 2C8/9), inhibited DDS-NHY by 48 +/- 14 and 41 +/- 15%, respectively. The apparent Michaelis-Menten Km values for DDS-NHY by cloned CYP2C8, CYP2C9, CYP2C18, and CYP2C19 were 75 microM, 31 microM, 25 microM, and greater than 1 mM, respectively. CYP3A4 and CYP2E1 were incapable of DDS-NHY at 4 microM DDS. S-mephenytoin (360 microM) activated DDS-NHY by human liver microsomes and by CYP2C8 by 43 +/- 36 and 193 +/- 16%, respectively. This activation was cytochrome b5-dependent. In contrast, S-mephenytoin inhibited DDS-NHY by CYP2C9, CYP2C18, and CYP2C19 by 27 +/- 2, 49 +/- 1, and 32 +/- 4%, respectively. Because CYP2C18 and CYP19 are expressed at low concentrations in the human liver, these observations indicate that at clinical DDS concentrations, CYP2C9 is a major and CYP2C8 is a likely minor contributor to DDS-NHY in human liver microsomes.

AIDS-Related Opportunistic Infections↗

PubMedDate not supplied

Pharmacokinetics of dapsone and amino acid prodrugs of dapsone.

Amino acid amides of dapsone (DDS), a primary aromatic amine, have been synthesized as water-soluble, chemically stable prodrugs that target peptidase enzymes for cleavage to the parent drug in vivo. The pharmacokinetics of DDS, monoacetyldapsone (MADDS; a known metabolite), and various L- and D-amino acid derivatives of DDS were investigated in New Zealand white rabbits after intravenous administration. DDS and MADDS exhibit reversible kinetics and establish a pseudoequilibrium in vivo. In this study, the analytical procedure assayed for both DDS and MADDS, with formation of MADDS accounting for approximately 25% of the clearance of DDS. The L-amino acid derivatives of DDS were rapidly (t1/2 < 2 min) and quantitatively converted to DDS after intravenous administration to rabbits. Data are consistent with conversion of the L-amino acid amides to DDS by the action of stereospecific aminopeptidase enzymes and suggest that they would be good prodrug candidates. The corresponding D-amino acid derivatives were also quantitatively converted to DDS, but the half-lives ranged from 30 to 60 min. The specific mechanism for conversion of the D-amino acid amides to DDS is unknown.

Amino Acids↗

PubMed1963