Sulfamethazine acetylation

Reeves PT, Minchin RF, Ilett KF, Induction of sulfamethazine acetylation by hydrocortisone in the rabbit. Drug Metab. Dispos. 1988 16 104-109. 

R. Whelpton, G. Watkins and S.H. Curry, Bratton-Marshall and liquid-chromatographic methods compared for determination of sulfamethazine acetylator status, Clin. Chem., 1981, 27, 1911-1914. 

Tissues from both rapid and slow acetylator rabbits have been investigated. The capacity to acetylate sulfamethazine in tissues of a rapid acetylator rabbit is located primarily in liver, gut mucosa, and lung it is also present in thymus, ovary, spleen, uterus, adrenal, leukocytes, kidney, bone marrow, salivary gland, pancreas, pineal, erythrocytes, and brain. Sulfamethazine-acetylating activity is undetectable in eletal muscle, fat, skin, and plasma. In contrast, bver and gut mucosa from a slow acetylator rabbit contain low or undetectable levels of sulfamethazine-acetylating activity as expected, while certain extrahepatic tissues, in particular spleen, kidney, and pineal remain at levels found in the rapid acetylator, and thus do not reflect the acetylator phenotype of the animal These findings are shown in Fig. 6 for four tissues obtained from a series of rabbits with a spectrum of sulfamethazine-acetylating activities from very rapid to very slow acetylators. It should be noted that activity levels in gut mucosa correlate well with that in liver for rapid acetylator animals (C, F, G, and H) but reach a minimal, relatively invariant value for animals at the opposite end of the spectrum. 

Fig. 6. Distribution of sulfamethazine-acetylating activity in rabbit liver (black bar), gut mucosa (cross-hatched bar), spleen (dotted bar), and kidney (white bar).

Acetyl isoniazid or acetyl N -sulfamethazine Acetyl CoA Competitive... 

Acetylated MS-222 was found in much higher concentrations in the urine than in the blood of rainbow trout. This suggests that the kidney concentrated the drug metabolite, or that MS-222 was acetylated in the kidney and excreted in the urine (28). Weber (31) stated that acetylation of p-aminobenzoic acid and sulfamethazine is catalyzed by most of the tissues in the body. He showed that in rabbits the acetylation of these amines by the kidney of rabbit is a small percentage of the total acetylation capability, but that the kidney is involved in this biotransformation. 

The extent to which a sulfonamide is acetylated depends upon the drug administered and the animal species. Acetylsulfathiazole is the principal metabolite found in the urine of cattle, sheep, and swine after enteral or parenteral administration of sulfathiazole. However, sheep can acetylate only 10% of the dose, while cattle can acetylate 32%, and swine 39%. When sulfamethazine was administered intravenously or orally to cattle, the animals eliminated 11% or 25% of the dose, respectively, in urine as N" -acetylsulfamethazine. The increased acetylation that occurred following tlie oral administration may be related to the increased exposure of sulfamethazine to liver enzymes following its absorption into the portal circulation. The acetylation rate may also be affected by the health status of an animal. Tims, cows suffering from ketosis in cows acetylate sulfonamides at much lower extent. 

Sulfamethazine is metabolized by hydroxylation at the 5 and 6 positions of the pyrimidine ring and by acetylation-deacetylation pathways. After hydroxylation, the metabolites may become glucuronidated and also acetylated (204). In cows and calves (205), sulfamethazine is extensively metabolized into hydroxyl derivatives and, to a lesser extent, acetylated into N -acetylsulfamethazine. Hydroxylation of the 6-methyl group to form 6-hydroxymethylsulfamethazine dominates hydroxylation at the 5 position. 

Laying hens eliminate sulfamethazine rapidly by metabolic pathways that include both hydroxylation and acetylation (205). Within 3 days of the last sulfamethazine administration, plasma concentrations of the drug and its metabolites fell below the level of 0.02 ppm. In eggs, increase of sulfamethazine in egg white and yolk occurs during the whole medication period. Residues of the parent drug could be detected in the eggs laid 7 days after the cessation of the administration (210). Traces of N -acetylsulfamethazine and hydroxyl metabolites were also detectable up to day 3 after drug withdrawal. 

When sheep were injected intravenously with a single dose of 107 mg sulfamethazine/kg bw, total residues in muscle, liver, kidney, and fat declined rapidly to reach, after 5 days of withdrawal, a value of less than 0.1 ppm (211). In fish, the main metabolite is N" -acetylsulfamethazine, although sulfamethazine is hydroxylated and acetylated only to a small degree. 

In other cases, the same disease states exert a different effect on drug pharmacokinetics depending on the drug and the animal species (41). Elimination of sulfadimethoxine or amoxycillin from pigeons was distinctly accelerated in case of Coccidia (42) or Salmonella infection (43). However, significant differences in the residue profile, compared to healthy chickens, were observed neither in that of sulfamethazine nor in that of its acetyl metabolite after oral administration to chickens infected with Coccidia (44). 

It should be noted that in the hamster the situation is the reverse, with p-aminobenzoic acid and p-aminosalicylic acid being polymorphically acetylated and sulfamethazine and procainamide monomorphically acetylated. 

Acetyl transferease NAT2 Slow, rapid acetylators Isoniazid Sulfamethazine Procainamide Sufasalazine Paraminosalicylic acid Hydralazine Toxic neuritis, lupus erythematosus. (Slow acetylators)... 

The metabolism of a number of sulfonamides, such as sulfanilamide. sulfamethoxazole (Gantanol). sulfisoxa-zx>le (Gantrisin). sulfapyridine (major metabolite from azo reduction of sulfasalazine. Azulfidine), and sulfamethazine. " " occurs mainly by acetylation at the N-4 position. With sulfanilamide, acetylation also takes place at the sul-... 

For CES, there appear to be no regional differences in the small intestine for the N-acetyltransferase (NAT) activity [108]. The presence ofboth NAT isozymes has been demonstrated in the human gut mucosa by using the prototypical substrates p-aminobenzoic acid (NAT1) and sulfamethazine (NAT2) [109, 110]. The active metabolites 5-aminosalicylic acid and sulfapyridine of the prodrug sulfasalazine undergo extensive presystemic acetylation in the small intestine [111]. 

Gilligan, D., Rlummer, N. Comparative solubilities of sulfadiazine, sulfamerazine and sulfamethazine and their N4-acetyl derivatives at varying pH levels. Proc. Soc. Exp. Biol. Med. 1943, 53, 142-145. 

The distributions of C-labeled compounds in the tissues (Table III) and urine (Table IV) indicate that the metabolism of C-sulfamethazine in the orally and intravenously dosed cows was similar. Four metabolites (fractions II, III, IV and XII) were observed in the urine after only one route of administration however, each of these metabolites accounteid for 1.4% or less of the total C-activity in the urine, and it is possible they were present in the urine of the other animal in trace amounts but below the level of detection for the methodology used in these studies. Most of the types of sulfamethazine metabolism observed in these animals has been reported before. However, not previously identified were the metabolites resulting from transformations at two sites on the molecule (e.g. N -acetylation and hydroxylation of heterocylic ring ... 

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. 

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. 

Nouws JEM, Mevius D, Vree TB, Baakman M, Degen M, Pharmacokinetics, metabolism, and renal clearance of sulfadiazine, sulfamerazine, and sulfamethazine and of their N-4 acetyl and hydroxy metabolites in calves and cows, Am. J. Vet. Res. 1988 49 1059-1065. 

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