M. W. Tijhuis

Pharmacokinetics and mechanism of renal excretion of short acting sulphonamides and N4-acetylsulphonamide derivatives in man

SummaryThe 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 sulphathiazole. 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%.

Isolation and identification of 4-hydroxysulfamerazine and preliminary studies on its pharmacokinetics in dogs

For the following compounds: sulfamerazine, 4-hydroxysulfamerazine, N4acetylsulfamerazine, N4-acetyl4-hydroxysulfamerazine, the following data are reported: biosynthesis in the dog, isolation, identification by MS and NMR, TLC (Rf values) and HPLC (capacity factors and molar extinction), half-life of elimination, metabolism, renal excretion and protein binding in dog. Dogs are unable to acetylate sulfamerazine, but eliminate predominantly by hydroxylation of the N1-substituent. Administered N4-acetylsulfamerazine is predominantly eliminated by deacetylation to sulfamerazine which in turn is hydroxylated. The renal clearances of sulfamerazine and N4-acetylsulfamerazine in the dog are identical. The renal excretion of both compounds proceeds by the passive processes of glomerular filtration and tubular reabsorption.4-Hydroxysulfamerazine and its glucuronide have a higher renal clearance than sulfamerazine.

Effects of methoxy groups in the NI-substituent of sulfonamides on the pathways of elimination in man. The acetylation-deacetylation equilibrium and mechanisms of renal excretion of sulfisomidine, sulfamethomidine and sulfadimethoxine.

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 N1-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 N1-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 sulfadimethoxine 34.6±10.4 h.

The acetylation-deacetylation equilibrium of sulfadimidine in ruminant calves.

Plasma disappearance curves of sulfadimidine (SDM) in calves show at high doses a pattern resembling that of capacity-limited elimination. The half-life of the first part of the elimination phase of SDM when administered at high doses ranged between 6.4 and 11.5 h, while that of the terminal end of the plasma concentration-time curves was similar to that obtained at a low level application, ranging between 2.5 and 6.0 h. The percentage of N4-acetylsulfadimidine (N4-SDM) in plasma was low, viz. 2.2 to 5.8% of the total sulfadimidine concentration measured. The acetylation-deacetylation equilibrium was established within 3 h p.i. The N4-SDM plasma concentration-time curves were parallel to those of SDM beyond 3 h p.i. At high doses (66-235 mg/kg) the percentage of N4-SDM was slightly higher than that found at the low dose level. A small proportion of N4-acetylsulfadimidine, injected as the parent compound, was deacetylated to SDM. The intrinsic elimination half-life of N4-SDM was 0.9 h. It may be concluded that ultra-trace concentrations of N4-SDM, left in edible tissues of ruminants at slaughter, have in case of negative sulfonamide-sensitive bioassays no significance for the public health.

The effect of the molecular structure of closely related N1-substituents of sulfonamides on the pathways of elimination in man

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.