The contribution of N-hydroxylation and acetylation to dapsone pharmacokinetics in normal subjects

May, David G.; Porter, James A.; Uetrecht, Jack; Wilkinson, Grant R.; Branch, Robert A.

doi:10.1038/clpt.1990.204

Cited by 64 publications

(52 citation statements)

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“…113 Risk of developing side effects, such as neurotoxicity or haemolytic anemia, to dapsone therapy is very similar to that described for the sulphonamides. 117 The most severe incidence of toxicity occurred in individuals with a slow acetylator phenotype who are rapid hydroxylators, which is consistent with the role each pathway has in the activation and detoxification of the drug. 118 While slow acetylators are at a greater risk of toxicity from sulphonamides and dapsone, other therapeutic agents exhibit increased incidence of adverse reactions in rapid acetylators.…”

Section: Nat and Drug Responsesupporting

confidence: 65%

Pharmacogenetics of the arylamine N-acetyltransferases

et al. 2002

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The arylamine N-acetyltransferases (NATs) are involved in the metabolism of a variety of different compounds that we are exposed to on a daily basis. Many drugs and chemicals found in the environment, such as those in cigarette smoke, car exhaust fumes and in foodstuffs, can be either detoxified by NATs and eliminated from the body or bioactivated to metabolites that have the potential to cause toxicity and/or cancer. NATs have been implicated in some adverse drug reactions and as risk factors for several different types of cancers. As a result, the levels of NATs in the body have important consequences with regard to an individual's susceptibility to certain druginduced toxicities and cancers. This review focuses on recent advances in the molecular genetics of the human NATs.

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Section: Nat and Drug Responsesupporting

confidence: 65%

Pharmacogenetics of the arylamine N-acetyltransferases

et al. 2002

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“…The V/F of dapsone reported for healthy and HIV-infected adults ranges from 0.7 to 1.5 liter/kg (8,9,28). The mean V/F for the children observed in this study was higher than that reported for adult subjects and was highly variable, with a fourfold difference between the lower and higher values.…”

Section: Discussioncontrasting

confidence: 52%

Pharmacokinetics of dapsone in human immunodeficiency virus-infected children

Gatti

Loy

Casazza

et al. 1995

Antimicrob Agents Chemother

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Dapsone, administered at various doses and schedules, has been proven to be a safe and effective alternative to trimethoprim-sulfamethoxazole for prevention of Pneumocystis carinii pneumonia (PCP) in adults with human immunodeficiency virus (HIV) infection. Dapsone is also recommended by the Centers for Disease Control for PCP prophylaxis in HIV-infected children. However, the suggested dosage regimen is based upon clinical experience with children with leprosy and dermatitis herpetiformis rather than pharmacokinetic and pharmacodynamic data obtained from the target patient population. In order to determine a rational dosage regimen that could be tested in clinical studies aimed at the evaluation of dapsone for the prevention of PCP in HIV-infected children, we studied the pharmacokinetics of dapsone following a 2-mg/kg of body weight oral dose in twelve HIV-positive children aged 9 months to 9 years. Plasma was collected at the following times after dapsone administration: 0, 2, 4, 6, 12, 24, 48, 72, and 96 h. The levels of dapsone in plasma were determined by high-performance liquid chromatography. Data were analyzed by noncompartmental methods. Expressed as means ؎ standard deviations (ranges), the pharmacokinetic parameters were as follows: peak concentration in plasma, 1.12 ؎ 0.48 (0.44 to 1.81) mg/liter; time to peak concentration in plasma, 3.8 ؎ 1.3 (2 to 6) h; half-life at elimination phase, 24.2 ؎ 7.1 (14.4 to 35.0) h; clearance from plasma divided by bioavailability (CL/F), 1.15 ؎ 0.67 (0.37 to 2.63) ml/min/kg; and volume of distribution divided by bioavailability (V/F), 2.25 ؎ 1.20 (1.00 to 4.57) liters/kg. Oral CL correlated negatively with age (r ‫؍‬ 0.614 and P ‫؍‬ 0.034), as did V (r ‫؍‬ 0.631 and P ‫؍‬ 0.028). As a consequence of the high interindividual variability in growth retardation, pharmacokinetic parameters correlated with measures of body development better than they did with age (e.g., for CL/F to height, r ‫؍‬ 0.765 and P ‫؍‬ 0.004, and for V/F to height, r ‫؍‬ 0.748 and P ‫؍‬ 0.005). Since oral CL from plasma and V were positively and highly correlated (r ‫؍‬ 0.898 and P ‫؍‬ 0.0001), a lower absolute F may be the cause, in part, of higher values for CL/F and V/F in smaller children. The results of this study warrant the testing of a 2-mg/kg dose of dapsone administered twice or thrice weekly to HIV-infected children. The monitoring of drug levels in plasma and dosage adjustment may be necessary for smaller children.

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“…This observation indicates that the arylhydroxylamine metabolites readily enter these cells and presumably autooxidize to their respective arylnitroso derivative prior to covalent adduction with proteins. The ability to detect the arylhydroxylamine metabolites of SMX (Cribb and Spielberg, 1992;van der Ven et al, 1994;van der Ven et al, 1995) and dapsone (Gordon et al, 1979;May et al, 1990;Mitra et al, 1995) in the urine of patients receiving these drugs suggests that the stability of these metabolites in blood is sufficient for distribution throughout the body after formation in the liver. Hence, dermal fibroblasts may be exposed to these arylhydroxylamine metabolites in vivo after formation in the liver and distribution to the skin.…”

Section: Discussionmentioning

confidence: 99%

Bioactivation, protein haptenation, and toxicity of sulfamethoxazole and dapsone in normal human dermal fibroblasts☆

Bhaiya

Roychowdhury

Vyas

et al. 2006

Toxicology and Applied Pharmacology

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Cutaneous drug reactions (CDRs) associated with sulfonamides are believed to be mediated through the formation of reactive metabolites that result in cellular toxicity and protein haptenation. We evaluated the bioactivation and toxicity of sulfamethoxazole (SMX) and dapsone (DDS) in normal human dermal fibroblasts (NHDF). Incubation of cells with DDS or its metabolite (D-NOH) resulted in protein haptenation readily detected by confocal microscopy and ELISA. While the metabolite of SMX (S-NOH) haptenated intracellular proteins, adducts were not evident in incubations with SMX. Cells expressed abundant N-acetyltransferase-1 (NAT1) mRNA and activity, but little NAT2 mRNA or activity. Neither NAT1 nor NAT2 protein were detectable. Incubation of NHDF with S-NOH or D-NOH increased reactive oxygen species formation and reduced glutathione content. NHDF were less susceptible to the cytotoxic effect of S-NOH and D-NOH than are keratinocytes. Our studies provide the novel observation that NHDF are able to acetylate both arylamine compounds and bioactivate the sulfone, DDS, giving rise to haptenated proteins. The reactive metabolites of SMX and DDS also provoke oxidative stress in these cells in a time-and concentration-dependent fashion. Further work is needed to determine the role of the observed toxicity in mediating CDRs observed with these agents.

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The contribution of N-hydroxylation and acetylation to dapsone pharmacokinetics in normal subjects

Cited by 64 publications

References 0 publications

Pharmacogenetics of the arylamine N-acetyltransferases

Pharmacogenetics of the arylamine N-acetyltransferases

Pharmacokinetics of dapsone in human immunodeficiency virus-infected children

Bioactivation, protein haptenation, and toxicity of sulfamethoxazole and dapsone in normal human dermal fibroblasts☆

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