Pharmacokinetics, N1-glucuronidation and N4-acetylation of sulfadimethoxine in man

Abstract

Sulfadimethoxine is metabolized by O-dealkylation, N4-acetylation and N1-glucuronidation. In man, only N1-glucuronidation and N4-acetylation takes place, leading to the final double conjugate N4-acetylsulfadimethoxine-N1-glucuronide. The N1-glucuronides are directly measured by high pressure liquid chromatography. When N4-acetylsulfadimethoxine is administered as parent drug, 30% of the dose is N1-glucuronidated and excreted. Fast acetylators show a shorter half-life for sulfadimethoxine than slow acetylators (27.8 +/- 4.2 h versus 36.3 +/- 5.4 h; P = 0.013), similarly the half-life of the N4-acetyl conjugate is also shorter in fast acetylators (41.3 +/- 5.2 h versus 53.5 +/- 8.5 h, P = 0.036). No measurable plasma concentrations of the N1-glucuronides from sulfadimethoxine are found in plasma. N1-glucuronidation results in a 75% decrease in protein binding of sulfadimethoxine. N4-acetylsulfadimethoxine and its N1-glucuronide showed the same high protein binding of 99%. Approximately 50-60% of the oral dose of sulfadimethoxine is excreted in the urine, leaving 40-50% for excretion into bile and faeces.

Isolation, identification and determination of sulfadiazine and its hydroxy metabolites and conjugates from man and Rhesus monkey by high-performance liquid chromatography

“…A similar difference in the N-glucuronidation was reported earlier; human urine contained the N,-glucuronide of sulfamethoxazole [10], which is absent in monkey urine [11]. Also in humans sulfadimethoxine is mainly glucuronidated at the N,-position [12], whereas in pigs it is only acetylated at the re position [13].…”

N2‐Glucuronidation and N4‐acetylation of sulphaphenazole by the turtlePseudemys scripta elegans

“…A similar observation is made for sulphadimethoxine (24). The turtle is able to 0-dealkylate the drug, while man is not and chooses the alternative NIglucuronidation pathway (23).…”

“…Species-dependent glucuronide conjugates have been reported for sulphadimethoxine (1, 2), which has been assigned NI-or N4-glucuronides. In sulphadimethoxine, the N1-glucuronidation in man is a slow process, leading to the long half-life of 30-40 h; nevertheless 40% of the dose is NI-glucuronidated and 15% Nracetylated (24). N-glucuronides have been reported as metabolites of sulphaphenazole in man (9,10,15,16,17).…”

Comparison of the metabolism of four sulphonamides between humans and pigs

“…Recently we were able to measure the N1-glucuronide conjugate of sulphadimethoxine and of sulfa-6-monomethoxine in the urine of man (10,12), but we were unable to find this metabolite in the urine of pigs (6). Instead sulphadimethoxine was completely N4-acetylated.…”