Pharmacokinetics, N1-glucuronidation and N4-acetylation of sulfamethomidine in humans

Abstract

Sulfamethomidine metabolism was studied in 6 volunteers. In humans, only N1-glucuronidation and N4-acetylation take place, leading to the final double conjugate N4-acetylsulfamethomidine N1-glucuronide. The N1-glucuronides were directly measured by high pressure liquid chromatography. Fast and slow acetylators show a similar half-life for sulfamethomidine (26 +/- 6 h) and its conjugates sulfamethomidine (26 +/- 6 h) and N4-acetylsulfamethomidine (36 +/- 16 h). Approximately 50-60% of the oral dose of sulfamethomidine is excreted in the urine, leaving 40-50% for excretion into bile and faeces. The main metabolite of sulfamethomidine is its N1-glucuronide, which accounts for 36 +/- 7% of the dose, followed by N4-acetylsulfamethomidine (16 +/- 8%). N1-glucuronidation results in a 75% decrease in protein binding of sulfamethomidine. N4-acetylsulfamethomidine and its N1-glucuronide showed the same high protein binding of 99%. The renal clearance of N4-acetylsulfamethomidine is 7.9 +/- 2.2 ml/min and approximately 20 times as high as that of the parent drug (0.46 +/- 0.16 ml/min). Total body clearance of sulfamethomidine is 4.5 +/- 0.9 ml/min and the volume of distribution in steady state 10.6 +/- 1.7 1. No measurable plasma concentrations of the N1-glucuronides from sulfamethomidine are found in plasma. This may be explained by renal glucuronidation after active tubular reabsorption.

Comparison of the metabolism of four sulphonamides between humans and pigs

“…It is clear that pigs do not possess the N1-glucuronidation pathway of sulphadimethoxine and sulphamethomidine as observed in man (10,17). Fig.…”

“…Sulphapyridine (11), sulphadiazine (15), sulphadimethoxine (10) and sulphamethomidine (17) with their metabolites were analysed by means of high-performance liquid chromatography (HPLC) as described elsewhere.…”

“…The presence of methoxy groups seems to be the first requirement for N1-glucuronidation, and secondly the 2 and 6 position of the pyrimidine group must be substituted (14,17,18,Vree et al HPLC screening, unpublished results). In general it can be stated that 0-glucuronidation carried out by liver UDPGtransferase is a relatively fast process (7) and 0-glucuronides can be detected in plasma (e.g.…”

“…The sulphonamide was administered orally in a gelatine capsule in a dose of 6-10 mg/kg. Blood and urine samples were collected as described in the particular studies (9,10,11,17).…”

“…The parent drug elicits extremely low renal clearance values, suggesting tubular reabsorption. This reabsorption process, followed by N1-glucuronidation, is then a relatively slow process, resulting in the almost identical long half-lives for sulpha-2,6-dimethoxine, sulphamethomidine and sulpha-6-monomethoxine (10,12,17). The reabsorption can be assumed to be carried out by the urate reabsorption pathway, because sulpha-2,6-dimethoxine and urate have some similarities in their molecular structures.…”