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Pigs are unable to form N1-glucuronides of sulphadimethoxine and sulphamethomidine, while humans are able to do so. Pigs and humans are able to oxidise sulphapyridine and form the O-glucuronide. The double conjugate N4-acetylsulphapyridine-O-glucuronide is formed in humans but not in pigs. Sulphadiazine is mainly acetylated in both humans and pigs. A hypothesis about N1-glucuronidation is presented.

Hydroxylated metabolites of sulphadimidine, sulphamerazine, sulphatroxazole, sulphamethoxazole, and sulphadiazine exhibited antimicrobial activity against Escherichia coli 28 PR 271 test strain ranging from 2.5 to 39.5 per cent of that of the parent drug. Trimethoprim addition potentiated the antimicrobial activity of these metabolites. N4-acetyl sulphonamide metabolites possessed no antimicrobial activity, nor did trimethoprim potentiated them.

The pharmacokinetics of sulphamethizole, sulphamethoxazole, sulphadiazine, sulphapyridine and sulphadimidine have been studied in man. Renal clearance values of the metabolite N4-acetylsulphonamide are 6 to 20 times higher than those of the corresponding parent compound. The renal clearance of sulphonamides is dependent on the urine flow. N4-Acetylsulphonamide concentration-time profiles for plasma and urine have been constructed for the sulphonamides. The percentage N4-acetylsulphonamide-time profiles for plasma are excellent tools for establishing the acetylator phenotype, while those constructed from urine samples are less useful. Evidence is obtained that sulphadimidine is metabolically processes by 2 different isoenzymes, while sulphadiazine, sulphapyridine and sulphamethoxazole are processes by 1 acetylating isoenzyme. Sulphamethizole is acetylated to very little extent.

An improved method of bioassay has been described for qualitative detection of sulphonamide and dapsone residues in kidney, muscle, urine, and milk. The sensitivity to the sulphonamides tested ranged from 0.01 to 0.3 micrograms/ml or g of tissue and from 0.003 to 0.0006 micrograms/ml for dapsone. No extraction procedures are needed.

Sulfadiazine, sulfamerazine, sulfadimidine and their corresponding N4-acetyl derivatives were administered to man. The percentages of acetylation and deacetylation, protein binding, half-lives of elimination and apparent and true renal clearance values were measured. Methyl substitution in the N1-pyrimidine ring favours acetylation by an additional N-acetyltransferase isoenzyme present in 'fast' acetylators only. Methyl substitution in the N1-pyrimidine ring favours renal clearance of the N4-acetylsulfonamide derivatives. The N1-substituent probably reinforces the binding of the N4-acetyl group to the active tubular transport mechanism. The renal clearance of these sulfonamides is not dependent on the structure of the N1-substituent.

The pharmacokinetics of short acting sulphonamides and a series of N4-acetylsulphonamide derivatives has been investigated. Sulphonamides with a sulphur atom two atomic bond distances from the N1 atom are excreted by active tubular secretion, e.g. sulphamethizole, sulphaethidole and sulphathiasole. When the sulphur atom is replaced by an oxygen or nitrogen atom, active renal excretion no longer occurs. N4-acetylsulphonamides are excreted by active tubular secretion. The renal clearance values of the N4-acetylsulphonamides are not influenced by the substituent at the N1 position. Two groups of N4-acetylsulphonamides can be distinguished. One has a T1/2 of 4-6 h and a renal clearance value of 20-60 ml/min and the second has a T1/2 of 10-20 h and a renal clearance of less than 10 ml/min. N4-acetylsulphonamides are deacetylated to the extent of about 5%.

Sulfisomidine, sulfamethomidine, sulfadimethoxine and their corresponding N4-acetyl derivatives were administered to man. The percentages of acetylation and deacetylation and those of protein binding, the half-lives of elimination and the apparent and true renal clearance values were measured. No acetylation phenotype could be demonstrated in these compounds. Methoxy substitution in the NI-pyrimidine group of sulfisomidine affects predominantly the renal clearance value and mechanism of the parent compound but has no influence on the renal clearance of the N4-acetyl derivatives. The renal clearance value of sulfisomidine is 232 +/- 33 ml/min, of sulfamethomidine 21.60 +/- 16.4 ml/min and of sulfadimethoxine 10.87 +/- 10.44 ml/min. The renal clearance values of the corresponding N4-acetylsulfonamide derivatives are 314 +/- 91 ml/min, 342 +/- 63 ml/min and 202 +/- 65 ml/min respectively. Tubular reabsorption, caused by methoxy substitution in the NI-pyrimidine ring, lowers the rate of elimination and increases the half-life. The half-life of sulfisomidine is 8.5 +/- 0.5 h, of sulfamethomidine 27.8 +/- 5.3 h and of sufadimethoxine 34.6 +/- 10.4 h.