Dapsone acetylation

Ellard GA, Gammon PT, Savin JA, Tan RS-H. Dapsone acetylation in dermatitis herpetiformis BrJ Dermatol (1974) 90,441-4... 

Acedapsone (127), which is conveniently prepared by acetylation of dapsone, was intended to be a prodrug. Leprous patients being treated with dapsone were observed to have a lower incidence of malaria and acedapsone was made to capitalize on this observation. It, indeed, has both antileprotic and antimalarial activity. 

Frequency 45-65% of Caucasians and African Americans 10-15% of Asians Slow inactivation of drugs such as isoniazid (for tuberculosis), dapsone (for leprosy), and hydralazine (for high blood pressure), leading to toxicity from the drug at doses well tolerated in people with rapid acetylator phenotype Clinical consequences depend on the specific side effects of the drugs... 

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. 

Acetylation Acetyl-CoA /V-Acetyltransferase (cytosol) Amines Sulfonamides, isoniazid, clonazepam, dapsone, mescaline... 

Although the two forms of the enzyme have preferred substrates, there is overlap between them such that no substrate seems to be exclusively acetylated by one or the other. Some preferred NAT1 substrates are p-aminobenzoic acid and p-aminosalicylic acid and sulfanilamide, whereas preferred substrates for NAT2 include isoniazid, hydralazine, procainamide, and dapsone. 

Dapsone (4,4 -diaminodiphenylsulfone) has been widely used for phenotyping with respect to acetylation by NAT-2 however, the drug is also N-hydroxylated. Formation of the hydroxylamine metabolite by human liver microsomes was found to be selectively mediated by CYP3A (286) this led to the development of a zero- to eight-hour urinary metabolic recovery ratio approach [dapsone hydroxylamine (dapsone + dapsone hydroxylamine)] to quantitatively assess this pathway of metabolism (287,288). Subsequently, the trait measure has been applied as part of a cocktail approach (35) in a number of studies investigating the putative role of CYP3A as a risk factor in cancer (289-291) and other disease states (288,292,293). 

Bluhm RE, Adedoyin A, McCarver DG, et al. Development of dapsone toxicity in patients with inflammatory dermatoses activity of acetylation and hydroxyl-ation as risk factors. Clin Pharmacol Ther 1999 65 598-605. 

O Neil WM, Drobitch RK, MacArthur RD et al. (2000) Acetyla-tor phenotype and genotype in patients infected with HIV discordance between methods for phenotype determination and genotype. Pharmacogenetics 10 171-182 Queiroz RH, Dreossi SA, Carvalho D (1997) A rapid, specific, and sensitive method for the determination of acetylation phenotype using dapsone. J Analytical Tox 21 203-207... 

Dapsone Bulk TLC albumin, 50 g/ml rt-acetyl trypiophan Dissolve in methanol Silica... 

Following a single oral dose of 1 g given to 12 slow acetylators and 11 rapid acetylators (determined with reference to dapsone), the following mean peak plasma concentrations ( ig/ml, time in hours) were reported ... 

Drugs that have been shown to be subject to phar-macogenetic differences in biotransformation include debrisoquine, perhexiline, phenformin, mephenytoin, tolbutamide, dapsone, isoniazid and sulfadimidine. The latter three drugs are primarily biotransformed by Y-acetylation, a pathway for which about 50 /o of the United Kingdom population can be classified as slow acetylators and the rest as fast acetylators. 

To what extent phenotype (fast versus slow acetyla-tors) affects the metabolism of dapsone is controversial. Since dapsone is acetylated in the liver, an effect might be anticipated (SEDA-4, 217) (40), but has not been demonstrated. 

Caffeine has been used to phenotype NAT2 using the urinary ratio of the caffeine metabolite, 5-acetylamino-6-formylamino-3-uracil (AFMU), or 5-acetyl-6-amino-3-uracil (AAMU), to various other caffeine metabolites (e.g., 1-methylxanthine (IX), 1-methylurate (lU)) or combinations of metabolites. Dapsone and sulfamethazine have also been used to phenotype NAT2. 

The sulfones are distributed throughout total body water and are present in all tissues. They are retained in skin and muscle and especially in liver and kidney. The sulfones persist in the circulation for a long time because of reabsorption from the bile periodic interruption of treatment is advisable for this reason. Dapsone is acetylated in the liver by the same enzyme that acetylates isoniazid. Daily administration of50-100 mg results in serum levels exceeding the usual minimal inhibitory concentrations, even in rapid acetylators, in whom the serum t of dapsone is shorter than usual. 

Dapsone has been prepared by a number of procedures (1,48). One procedure employs the reaction of l-chloro-4-nitrobenzene with excess sodium sulfide to give the 4-amino-4 -nitrodiphenyl sulfide. This compound, after acetylation of the amino group, is oxidized with H2O2 to the sulfone. The nitro group is then reduced to amino, and hydrolysis of the acetyl gives the product. 

Sulfonamides having a free j )-amino group are readily assayed by titration with nitrous acid. The sulfonamide function may also be titrated with base, such as lithium methoxide. The majority of the sulfas listed in the U.S. Pharmacopeia XXII, however, are assayed by chromatographic methods, particularly high performance liquid chromatography (49). Sulfonamides for which assays are listed in the U.S. Pharmacopeia XXII-National Formulary XVII include the following sulfacetamide, sulfabenzamide, sulfadiazine, sulfadoxine, sulfamerazine, sulfamethazine, sulfamethizole, sulfamethoxazole, sulfapyridine, sulfasalazine, sulfathiazole, sulfinpyrazone, sulfis ox azole, sulfisoxazole acetyl, sulfisoxazole diolamine, sulfoxone, triple sulfa, dapsone, and various combinations with prednisolone, pyrimethamine, and trimethoprim. 

D. Pharmacokinetics. Absorption of dapsone is delayed peak plasma levels occur between 4 and 8 hours after ingestion. The volume of distribution (Vd) is 1.5 Ukg. Protein binding is approximately 70-90%. Dapsone is metabolized by two primary routes, acet ation and P-450 oxidation. Both dapsone and its acetylated metabolite undergo enterohepatic recirculation. The average elimination half-life is 30 hours after a therapeutic dose and as long as 77 hours after an overdose. (See also Table 11-59.)... 

Pathogenesis Dapsone is metabolized either by acetylation to non-toxic acetyldapsone or by N-hydroxylation by multiple CYP isoenzymes to toxic hydroxylamines [51 ]. The latter are thought to be responsible for methemoglobinemia and hemolysis. 

The pathophysiology of the dapsone syndrome is unclear, but dapsone metabolites may act as haptens, resulting in the formation of antidapsone antibodies. Dapsone is metabolized primarily via A/-acetylation and /V-hydroxylation. The A -hydroxylation pathway is thought to be the initial step in the formation of toxic intermediate... 

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