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PubMed1990

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

The relative importance of N-hydroxylation and acetylation of dapsone to the oral clearance of dapsone (100 mg) was investigated in seven healthy volunteers. Plasma dapsone and monoacetyldapsone concentrations rose rapidly with subsequent similar monoexponential elimination. The oral clearance of dapsone was low (33 +/- 14 ml/min), with a threefold variability. Four subjects were identified as fast acetylators; however, differences in acetylation did not explain the variability in oral clearance. The cumulative urinary recoveries of dapsone and its hydroxylamine were approximately 20% of the dose. The formation clearance of hydroxylamine, which exhibited a tenfold intersubject variability, was closely associated with the oral clearance of dapsone (r = 0.96). Thus, the formation of the hydroxylamine is more important than acetylation in determining dapsone's intersubject variability in oral clearance. Variation in N-hydroxylation may have clinical consequences, because the hydroxylamine is considered to be important in dapsone-mediated toxicity.

Acetylation↗
PubMed1995

Lower survival in AIDS patients receiving dapsone compared with aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia. Study Group.

A randomized, unblinded study compared aerosolized pentamidine, 300 mg every month, and dapsone, 50 mg/day, for secondary prophylaxis of pneumocystosis in 196 AIDS patients. The study was prematurely discontinued due to excess mortality in the dapsone group. After a mean follow-up of 13 +/- 6.4 months, 22 (21%) of 103 patients in the pentamidine group were dead compared with 39 (42%) of 93 receiving dapsone; the estimated mortality rates at 18 months were 24.6% and 53.1%, respectively (P < .003, log-rank test). A negative interaction was observed between zidovudine and dapsone (P < .049, interaction test of Cox model), and the mean CD4 cell count during the study was lower in the dapsone (49 +/- 61/mm3) than in the pentamidine group (83 +/- 88/mm3; P < .002, t test). The lower survival might also be related to the oxidative effect of dapsone or to the addition of iron protoxalate to dapsone in this study. These results suggest caution in using dapsone as long-term therapy in advanced human immunodeficiency virus infection, especially in those receiving zidovudine.

AIDS-Related Opportunistic Infections↗
PubMed1997

Acute dapsone intoxication: a pediatric case report.

INTRODUCTION: There are many case reports of dapsone overdose in adults but only a few reports of dapsone-induced methemoglobinemia in children. We report a case of a three-year-old boy who developed prolonged recurrent methemoglobinemia following an ingestion of dapsone. METHODS: Case report. ETHICS: Not applicable. STATISTICS: Not applicable. RESULTS: This child developed significant symptoms of methemoglobinemia approximately two hours after ingesting dapsone 37.5 mg/kg. The initial methemoglobin level measured 2.5 hours after ingestion was 44%. The patient was treated with multiple doses of activated charcoal and methylene blue. Three doses of methylene blue reduced the methemoglobin level to 6% by approximately 16 hours after the overdose but the level rebounded to nearly 15% at 64 hours postingestion. DISCUSSION: Dapsone is a drug that is being used for a wide variety of clinical conditions. The primary clinical manifestation of dapsone overdose is methemoglobinemia. An important aspect of dapsone poisoning is its ability to produce methemoglobinemia, which is long lasting and which may recur following methylene blue therapy. Because of this, dapsone-poisoned children need to be monitored for two to three days.

Antimalarials↗
PubMed1994

Low activity of dapsone N-hydroxylation as a susceptibility risk factor in aggressive bladder cancer.

N-arylamines involved in the pathogenesis of bladder cancer, require metabolic activation via N-hydroxylation. The efficiency of in vivo N-hydroxylation of dapsone, a non-carcinogenic arylamine, may, therefore, provide a host susceptibility measure of risk of developing bladder cancer. To investigate this possibility, the dapsone recovery ratio, a phenotypic measure of the efficiency of dapsone hydroxylation, has been measured in a case control study in an urban UK population, comparing patients with aggressive bladder cancer (n = 33), non-aggressive bladder cancer (n = 60) and controls (n = 108). Dapsone recovery ratio in controls exhibited a unimodal distribution. Patients with aggressive bladder cancer had a similar distribution but significantly lower mean value (p < 0.005). Logistic regression analysis, controlling for sex, age, smoking habit and alcohol consumption confirmed a significant (p < 0.05) association between the dapsone recovery ratio and aggressive bladder cancer. Subjects in the lowest tertile of dapsone recovery ratio had a relative risk to 5.4-fold greater than subjects in the upper tertile (p < 0.009), and a trends test was significant (p < 0.001). There was no significant association between dapsone recovery ratio and non-aggressive bladder cancer. These results do not support the hypothesis that the drug metabolizing enzymes involved in dapsone N-hydroxylation are involved in causing bladder cancer. Instead, they suggest the opposite, the observation that low enzyme activity was associated with increased risk is consistent with this enzyme providing a detoxification mechanism for environmental procarcinogens.

Case-Control Studies↗
PubMed1990

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

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.

Cimetidine↗
PubMedDate not supplied

Dapsone-induced sulfone syndrome.

OBJECTIVE: To report a patient with dapsone-induced sulfone syndrome. CASE SUMMARY: A 42-year-old HIV-infected African American man developed fever, lymphadenopathy, exfoliative dermatitis, hepatitis, and methemoglobinemia 4 weeks after starting dapsone. Complete resolution of symptoms and laboratory abnormalities occurred with cessation of dapsone therapy. DISCUSSION: Sulfone syndrome is not a well-known sequela of dapsone therapy. It is not dose-related, usually occurs in doses of 50-300 mg/d, all cases occur within 2 months of starting dapsone, all patients have fever, and most patients will develop rash and evidence of hepatic injury. The temporal relationship between dapsone therapy and onset of clinical symptoms and objective data led us to believe that dapsone caused sulfone syndrome in our patient. An objective causality assessment revealed that the adverse drug event was probable. CONCLUSIONS: Although sulfone syndrome appears to be relatively uncommon, healthcare practitioners must be aware of the potentially fatal syndrome associated with dapsone use.

Adult↗
PubMed1999

Pharmacokinetics of trimetrexate and dapsone in AIDS patients with Pneumocystis carinii pneumonia.

The objective of this study was to determine the pharmacokinetics of trimetrexate and dapsone in AIDS patients with moderate to severe pneumocystis pneumonia. Trimetrexate, leucovorin, and dapsone were administered for 21 +/- 3 days in the following doses: trimetrexate glucuronate, 45 mg/m2; leucovorin, 20 mg/m2; and dapsone, 100 mg daily. The pharmacokinetics of trimetrexate, dapsone, and dapsone's metabolite, monoacetyldapsone, were determined at three separate periods over the course of treatment. Serial blood samples were obtained over 24 hours after dosing and analyzed for trimetrexate, dapsone, and monoacetyldapsone, and pharmacokinetic parameters were determined. The mean parameters obtained for the early, mid-, and late collection periods were the following: trimetrexate: t1/2 = 8.29, 9.15, 10.00 hr; AUC = 16.85, 22.38, 24.49 mg.hr/l; CI = 5.58, 4.14, 3.96 l/hr, respectively. DDS: t1/2 = 14.99, 16.59, 15.13 hr; AUC = 30.60, 35.29, 36.08 mg.hr/l; CI = 3.82, 3.49, 3.01 l/hr, respectively. Monoacetyldapsone: t1/2 = 20.25, 18.66, 16.32 hr; AUC = 24.05, 24.06, 23.86 mg.hr/l, respectively. No statistically significant changes in pharmacokinetics for trimetrexate or dapsone were observed over the 21 +/- 3 day course of treatment. The results suggest that there are no major interactions between trimetrexate and dapsone when administered together in acutely ill patients.

AIDS-Related Opportunistic Infections↗
PubMed2000

[Effect of dapsone on survival in HIV infected patients: a meta- analysis of finished trials].

BACKGROUND: The aim of the study was to estimate the effect of dapsone on survival in HIVinfected patients. METHOD: The method was a metaanalysis. Data searches used MEDLINE, AIDS TRIALS, and AIDS DRUGS databases from 1983 to January 1996, clinical trials registries of appropriate collaborative research groups, abstract books of International Conferences on AIDS and infectious diseases between 1988 and 1996, references listed within selected articles and active experts in HIV infection. Were considered as eligible: randomized clinical trials, conducted in adults, with one arm evaluating dapsone as prophylactic agent for Pneumocystis Carinii Pneumonia (PCP). Each primary investigator was asked to provide the most recent aggregated study data by completing a standardized questionnaire and to provide files of individual patient data whenever possible. RESULTS: Overall, 17 trials (4343 patients) were eligible for the metaanalysis. The analysis of all available aggregated data included 16 trials (4267 patients) and showed no deleterious effect of dapsone on survival: OR=1.11, 95% Confidence Interval (CI)=0.961.29. There was no evidence of heterogeneity among studies (p=0.50). The analysis of individual data included 10 trials (3115 patients) (OR for aggregated data from those trials=1.10, CI=0. 931.29) and confirmed the absence of deleterious effect of dapsone on survival: stratified Hazard Ratio=1.12, CI=0.991.27 (logrank test: p=0.08). In this subsample, there was evidence of a deleterious effect of dapsone used as secondary prophylaxis. However, this result did not remain when the trial reporting the greatest negative effect of dapsone on survival was omitted. CONCLUSION: Dapsone may be used safely as a primary prophylactic regimen for PCP or toxoplasmosis. However, no definitive recommendation can be made for the use of dapsone as secondary PCP prophylaxis.

AIDS-Related Opportunistic Infections↗
PubMedDate not supplied

Dapsone-induced photodermatitis in a patient with linear IgA dermatosis.

Dapsone (4, 4' diaminodiphenylsulfone) is an efficient antiinflammatory agent. Its therapeutic use may result in a variety of adverse effects. The most frequent unwanted reactions are hemolytic anemia and methemoglobinemia. By oral route dapsone is mainly metabolized to monoacetyldapsone (MADDS) and hydroxylamine dapsone (DDS-NOH). We report a 76-year-old female patient with linear IgA dermatosis who developed a dapsone-induced photosensitivity 8 weeks after initiation of sulfone therapy. She showed a widespread erythematous eruption in UV-exposed skin area. After clearing of skin lesions the photopatch test revealed positive reactions to dapsone, MADDS and DDS-NOH. Dapsone-induced photosensitivity to date has been described only in leprosy patients. We demonstrate for the first time that this adverse reaction is not restricted to leprosy and that dapsone metabolites may also contribute to the mechanism of photosensitivity like the parent sulfone. Dapsone-induced photosensitivity is a rare, not dose-related adverse effect of the sulfone and can also occur in patients with inflammatory skin disorders.

Aged↗
PubMed1992

Comparative trial of dapsone versus trimethoprim/sulfamethoxazole for primary prophylaxis of Pneumocystis carinii pneumonia.

The purpose of this study was to compare the efficacy and safety of dapsone and trimethoprim/sulfamethoxazole in the primary prophylaxis of Pneumocystis carinii pneumonia (PCP) in patients infected with the human immunodeficiency virus (HIV) and having less than 200 CD4-positive cells per ml. This was a prospective, randomized, open-label study, using dapsone (100 mg p.o.) or trimethoprim/sulfamethoxazole (160 mg/800 mg p.o.) daily. Patients who developed toxicity requiring discontinuation were offered to cross over to the other study drug. They continued in the study until development of toxicity or documented PCP. Eighty-six patients were enrolled; 47 were randomized to receive dapsone and 39 to receive trimethoprim/sulfamethoxazole. Discontinuation of initial study drug occurred in 33 of the dapsone group and 25 of the trimethoprim/sulfamethoxazole group. Rash was the most common reason for discontinuation. Ten patients crossed over from dapsone to trimethoprim/sulfamethoxazole (4 successfully) and 11 patients crossed over from trimethoprim/sulfamethoxazole to dapsone (6 successfully). During 1,638 patient-months of observation (862 for dapsone and 776 for trimethoprim/sulfamethoxazole), one episode of PCP developed in each group. Both dapsone and trimethoprim/sulfamethoxazole are efficacious for the prophylaxis of PCP in HIV-infected persons with less than 200 CD4-positive cells per ml, but are each associated with significant toxicity. Development of toxicity to one drug does not invariably predict toxicity to the other.

Adult↗
PubMed2007

Two randomized studies demonstrate the efficacy and safety of dapsone gel, 5% for the treatment of acne vulgaris.

BACKGROUND: A new aqueous gel formulation of dapsone has been developed that allows clinically-effective doses of dapsone to be administered topically with minimal systemic absorption. OBJECTIVES: The goal of these studies was to evaluate the efficacy and safety of dapsone gel, 5% in the treatment of acne. METHODS: Patients 12 years of age and older with acne vulgaris (N = 3010) participated in two identically-designed 12-week, randomized, double-blind studies of twice-daily monotherapy with dapsone gel, 5%, versus a vehicle gel. RESULTS: Dapsone gel-treated patients achieved superior results in terms of the investigator's global acne assessment (P < .001) and the mean percentage reduction in inflammatory, noninflammatory, and total lesion counts (all, P < .001) at week 12. Reductions in inflammatory lesion counts favoring dapsone gel over vehicle were apparent as early as 2 weeks and reached statistical significance by 4 weeks. No clinically significant changes in laboratory parameters, including hemoglobin, even among glucose-6-phosphate dehydrogenase-deficient patients, were observed. Adverse events were comparable between the treatment groups and rarely led to discontinuation. LIMITATIONS: Adjunctive topical treatments and their impact on acne were not studied in this trial. CONCLUSIONS: Dapsone gel, 5% appears to be an effective, safe, and well-tolerated treatment for acne vulgaris, with a rapid onset of action.

Acne Vulgaris↗
PubMed1999

Lack of relevance of the acetylator status on dapsone response in chronic autoimmune thrombocytopenic purpura.

Dapsone provides an alternative treatment for patients with chronic autoimmune thrombocytopenic purpura (AITP) who had inadequate response to conventional therapy. However, the efficacy of this treatment is achieved in only 50% of patients. Dapsone is partly metabolized by the polymorphic N-acetyltransferase 2% and 50% of Caucasian patients show a genetically determined slow acetylator phenotype. The aim of our study was to investigate the influence of the acetylator status on dapsone efficacy in patients with chronic AITP. Nineteen caucasian adults with chronic AITP, previously treated by dapsone, were included in the study. Acetylator phenotype was determined by using a caffeine urinary test. Among the fourteen fast acetylator patients, eight patients exhibited positive response to dapsone and six patients did not. Among the five slow acetylator patients, one patient displayed a positive response to dapsone. Comparison of data by using the Fisher's exact test did not reach statistical significance. Our results do not support a relationship between dapsone efficacy and acetylator status in adults with chronic AITP.

Acetylation↗
PubMed2002

High-performance liquid chromatographic method with ultraviolet detection for the determination of dapsone and its hydroxylated metabolite in human plasma.

A validated high-performance liquid chromatographic method with ultraviolet detection for the quantitative determination of dapsone (4,4'-diaminodifenyl sulfone, DDS) and a metabolite, hydroxylaminodapsone (4-amino-4-hydroxylaminodiphenyl sulfone, DDS-NOH), in human plasma is described. Human plasma was deproteinized with acetone and the clear supernatant solution after centrifugation was evaporated to dryness under a gentle stream of nitrogen at 70 degrees C. The residue was dissolved in a mixture of HPLC eluent and acetone (18:5 v/v) and an aliquot of this solution (50 microL) was injected onto the HPLC column. Dapsone, hydroxylaminodapsone and diazoxide as internal standard, were separated within 10 min by isocratic elution with water:acetonitrile:glacial acetic acid:triethylamine (80:20:1.0:0.5 by volume) as eluent. Detection was by ultraviolet at the wavelength of 295 nm. The within-day repeatability coefficients of variation were 3-5% for dapsone (0.301-20.0 mg/L, n = 5) and 3-5% for hydroxylaminodapsone (0.0948-6.32 mg/L, n = 5), whereas the between-day repeatability coefficients of variation were 3-8% (0.301-20.0 mg/L, n = 5) for dapsone and 4-10% for hydroxylaminodapsone (0.0948-6.32 mg/L, n = 5). The mean recoveries -were 92-107% (0.301-20.0 mg/L, n = 2), 80-82% (0.0948-6.32 mg/L, n = 2) and 88% (0.0200 mg/mL, n = 5), for dapsone, hydroxylaminodapsone and diazoxide, respectively. The average correlation coefficient of the calibration curve was 0.99988 (n = 5) for dapsone at a concentration range of 0.301-20.0 mg/L, whereas the average correlation coefficient of the hydroxylaminodapsone calibration curve was 0.99981 (n = 5) at a concentration range of 0.0948-6.32 mg/L. The limits of detection were 0.00200 and 0.0470 mg/L for dapsone and hydroxylaminodapsone, respectively. The method is suitable for drug level monitoring and for pharmacokinetic studies.

Calibration↗
PubMed1991

Mechanisms by which clofazimine and dapsone inhibit the myeloperoxidase system. A possible correlation with their anti-inflammatory properties.

The mechanisms by which two anti-leprotic drugs (clofazimine and dapsone), both with anti-inflammatory properties, inhibit myeloperoxidase (MPO)-catalysed reactions, were investigated. The disappearance of NADH fluorescence was used as an assay for its oxidation. Chloride stimulated the oxidation of NADH in the MPO-H2O2 system in a concentration-dependent manner (50-fold at 150 mM NaCl). Under these conditions Cl- is oxidized and the oxidant formed, presumably hypochlorous acid (HOCl), oxidizes NADH. Observations demonstrating the effect of the drugs on the MPO system, are: (1) Inhibition of Cl(-)-stimulated oxidation of NADH. (2) Inhibition of polypeptide modification in a model protein, thyroglobulin (TG). (3) Protection of MPO against loss of catalytic activity caused by chlorinating oxidants generated by the system. (4) Inhibition of haemoglobin oxidation. Only dapsone was active here. HPLC analyses suggested that the drugs were not significantly metabolized in the MPO-H2O2 system in the absence of Cl-. Bleaching of clofazimine was stimulated by Cl- in the MPO system, suggesting the involvement of HOCl. Clofazimine was found to be a more potent scavenger of HOCl than dapsone when the inhibition of NADH oxidation by reagent HOCl was used as an assay. This finding is also supported by HPLC analyses which indicated a greater sensitivity of HOCl for clofazimine than for dapsone. Relatively low concentrations of dapsone inhibited the oxidation of oxygenated haemoglobin (HbO2), suggesting that the drug was not metabolized to its N-hydroxylated derivative which is thought to be responsible for methaemoglobin (metHb) formation in vivo. It is proposed that the inhibitory mechanism of action of clofazimine is to scavenge chlorinating oxidants generated by the MPO-Cl(-)-H2O2 system, while dapsone converts MPO into its inactive compound II (ferryl) form. The different inhibitory mechanisms of clofazimine and dapsone towards the MPO system may contribute to the anti-inflammatory actions of the drugs.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1992

Inhibition of the human leukocyte enzymes myeloperoxidase and eosinophil peroxidase by dapsone.

Dapsone (4,4'-diaminodiphenylsulfone) is an antimicrobial substance that also has anti-inflammatory activity, which has been attributed to inhibition of the leukocyte enzyme myeloperoxidase (MPO). We observed that dapsone was a much better inhibitor of the eosinophil peroxidase (EPO) in an assay that measured peroxidase-catalyzed oxidation of tetramethylbenzidine at pH 5.4. To clarify the specificity and pH-dependence of dapsone inhibition of the purified enzymes under more physiologic conditions, we studied peroxidase-catalyzed oxidation of chloride to the antimicrobial and cytotoxic agent hypochlorous acid. Taurine was added as a trap for hypochlorous acid, to prevent inactivation of the enzymes or chlorination of dapsone by hypochlorous acid. Dapsone was much more effective as an inhibitor of both MPO and EPO when chloride rather than tetramethylbenzidine was the substrate. Inhibition of both enzymes was greater at neutral pH than at acid pH (pH 7 vs pH 5), but EPO was more sensitive to inhibition than MPO regardless of pH. Inhibition was increased by lowering chloride, raising hydrogen peroxide, or lowering the enzyme concentration. Inhibition was accompanied by irreversible loss of enzyme activity, which was correlated with loss of the heme absorption spectrum, indicating chemical modification of the enzyme active site. EPO, but not MPO, was partially protected against inactivation by adding physiologic levels of bromide along with chloride. The results suggest that dapsone could prevent MPO- and EPO-mediated tissue injury at sites where the peroxidase enzymes are secreted and diluted into the neutral pH environment of the tissue interstitial space. Dapsone might not inhibit peroxidase-mediated antimicrobial activity, which occurs at high enzyme concentrations in the acid environment of phagolysosomes.

Benzidines↗
PubMed1995

Metabolism of dapsone to its hydroxylamine by CYP2E1 in vitro and in vivo.

Dapsone toxicity is putatively initiated by formation of a hydroxylamine metabolite by cytochromes P450. In human liver microsomes, the kinetics of P450-catalyzed N-oxidation of dapsone were biphasic, with the Michaelis-Menten constants of 0.14 +/- 0.05 and 0.004 +/- 0.003 mmol/L and the respective maximum velocities of 1.3 +/- 0.1 and 0.13 +/- 0.04 nmol/mg protein/min (mean +/- SEM). Troleandomycin (40 mumol/L) inhibited hydroxylamine formation at 100 mumol/L dapsone by 50%; diethyldithiocarbamate (150 mumol/L) and tolbutamide (400 mumol/L) inhibited at 5 mumol/L dapsone by 50% and 20%, respectively, suggesting that the low-affinity isozyme is CYP3A4 and the high-affinity isozymes are 2E1 and 2C. Disulfiram, 500 mg, 18 hours before a 100 mg oral dose of dapsone in healthy volunteers, diminished area under the hydroxylamine plasma concentration-time curve by 65%, apparent formation clearance of the hydroxylamine by 71%, and clearance of dapsone by 26%. Disulfiram produced a 78% lower concentration of methemoglobin 8 hours after dapsone.

Adult↗
PubMed2004

Differential activation of CYP2C9 variants by dapsone.

Studies have shown that CYP2C9.1 mediated metabolism of flurbiprofen or naproxen is activated by co-incubation with dapsone. However, dapsone activation has not been examined in the known variant forms of CYP2C9. Six concentrations of flurbiprofen (2-300microM) or naproxen (10-1800 microM) were co-incubated with six concentrations of dapsone (0-100 microM) and with reconstituted, purified CYP2C9.1, CYP2C9.2 (R144C), CYP2C9.3 (I359L), or CYP2C9.5 (D360E), in order to assess degrees of activation. Dapsone increased the efficiency (V(m)/K(m)) of flurbiprofen 4'-hydroxylation by CYP2C9.1, CYP2C9.2, CYP2C9.3, and CYP2C9.5 by 8-, 31-, 47-, and 22-fold, respectively. In similar experiments using the substrate naproxen, dapsone increased the efficiency of naproxen demethylation 7-, 15-, 13-, and 22-fold, in CYP2C9.1, CYP2C9.2, CYP2C9.3, and CYP2C9.5, respectively. Also, dapsone normalized naproxen's kinetic profile from biphasic (CYP2C9.1 and CYP2C9.2) or linear (CYP2C9.3 and CYP2C9.5) to hyperbolic for all variant forms. Thus, amino acid substitutions of CYP2C9 variants affect the degree of dapsone activation in a genotype-dependent fashion. Furthermore, the degree of effect noted across variants appeared to be dependent on the substrate studied.

Alleles↗
PubMed1997

Effects of dual combinations of antifolates with atovaquone or dapsone on nucleotide levels in Plasmodium falciparum.

The triazine antifolates, cycloguanil and 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[(2,4,5-trichlorophenoxy)propy loxy]-1,3,5-triazine hydrobromide (WR99210), and their parent biguanide compounds, proguanil and N-[3-(2,4,5-trichlorophenoxy)propyloxy]-n-(1-methylethyl)-imido dicarbonimidic-diamine hydrochloride (PS-15), were tested in combination with a series of antimalarial drugs for synergism against Plasmodium falciparum growing in erythrocytic culture. Four synergistic combinations were found: cycloguanil dapsone, WR99210-dapsone, proguanil-atovaquone, and PS-15-atovaquone. Cycloguanil-dapsone or WR99210-dapsone had a profound suppressive effect on the concentration of dTTP in parasites while that of dATP increased. Depletion of dTTP is consistent with cycloguanil or WR99210 inhibiting dihydrofolate reductase and dapsone inhibiting dihydropteroate synthase. For the combinations proguanil-atovaquone and PS-15-atovaquone, the levels of nucleoside triphosphates (NTPs) and dNTPs were generally suppressed, suggesting that inhibition is not through nucleotide pathways but probably through another metabolic mechanism(s). Combinations of two synergistic pairs of antimalarial drugs, (proguanil-atovaquone)-(cycloguanil-dapsone) and (PS-15-atovaquone)-(WR99210-dapsone), were tested, and it was found that NTPs and dNTPs decreased much more than for a single synergistic combination. Dual synergistic combinations could play an important role in the therapy of multidrug-resistant malaria, just as combination chemotherapy is used to treat cancer.

Adenosine Triphosphate↗