Pharmacokinetics of sulfamethoxazole with its hydroxy metabolites and N4-acetyl-,N1-glucuronide conjugates in healthy human volunteers.

The aim of this investigation was to assess the pharmacokinetics of sulfamethoxazole (S) with its hydroxy metabolites (SOH, N4SOH, N4OH) and N4-acetyl- (N4) and N1-glucuronide (Sgluc) conjugates in 7 human volunteers after an oral dose of 800mg using a reversed phase gradient high-pressure liquid chromatography (HPLC) with UV detection. Sulfamethoxazole was rapidly and completely absorbed and metabolised to 5 metabolites. The plasma half-life (t½) of elimination varied for the parent drug and its metabolites between 9.7 and 15 hours. The protein binding of S (67.2%) increased when the compound was acetylated (88%), and decreased when it was oxidised at the 5-position (40%). Glucuronidation at the N1-position reduced the protein binding to 20%. The main metabolite in urine was N4 (43.5 ± 5.6%), followed by S (14.4 ± 3.4%). The percentages of the Sgluc (9.8 ± 2.6%), N4SOH (5.3 ± 1.0%), and SOH (3.0 ± 1.0%) did not differ statistically (p = NS). Only 2 to 3% of the N-hydroxylamine metabolite (N4OH) was excreted. The renal clearance values were: Sgluc 176 ± 33 ml/min, SOH 96.1 ± 23.7 ml/min, N4SOH 51.2 ± 10.4 ml/min, N4 35.2 ± 5.6 ml/min and S 2.7 ± 0.9 ml/min. The pharmacokinetic behaviour of the N1-glucuronide was reported for the first time. If one of the metabolites is responsible for the occurrence of side effects, then all metabolites must be included in this analysis.