PHARMACOKINETICS OF SULFAMETHOXAZOLE WITH ITS HYDROXY METABOLITES ANDN-4-ACETYL-GLUCURONIDE, N-1-GLUCURONIDE CONJUGATES IN HEALTHY-HUMAN VOLUNTEERS

The aim of this investigation was to assess the pharmacokinetics of su lfamethoxazole (S) with its hydroxy metabolites (SOH, N4SOH, N4OH) and N-4-acetyl- (N-4) and N-1-glucuronide (Sgluc) conjugates in 7 human v olunteers after an oral dose of 800mg using a reversed phase gradient high-pressure liquid chromatography (HPLC) with UV detection. Sulfamet hoxazole was rapidly and completely absorbed and metabolised to 5 meta bolites. The plasma half-life (t(1/2)) of elimination varied for the p arent drug and its metabolites between 9.7 and 15 hours. The protein b inding of S (67.2%) increased when the compound was acetylated (88%), and decreased when it was oxidised at the 5-position (40%). Glucuronid ation at the N-1-position reduced the protein binding to 20%. The main metabolite in urine was N-4 (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 re nal clearance values were: Sgluc 176 +/- 33 ml/min, SOH 96.1 +/- 23.7 ml/min, N4SOH 51.2 +/- 10.4 ml/min, N-4 35.2 +/- 5.6 ml/min and S 2.7 +/- 0.9 ml/min. The pharmacokinetic behaviour of the N-1-glucuronide w as reported for the first time. If one of the metabolites is responsib le for the occurrence of side effects, then all metabolites must be in cluded in this analysis.