Kinetic discrimination of three sulfamethazine acetylation phenotypes

The relationship between sulfamethazine disposition kinetics and acetylator phenotype was studied in 19 healthy subjects. Various kinetic parameters for sulfamethazine and its N4-acetylated metabolite were determined after a dose of a rapidly absorbed oral solution. When plotted on a frequency distribution histogram, the results exhibited a well-defined trimodal pattern for acetylation clearance values and overall elimination or metabolic rate constants. These data were consistent with the well-recognized acetylation polymorphism for sulfamethazine, except that they clearly subdivided the previously acknowledged "fast" acetylator mode into intermediate and rapid acetylator groups. The apparent distribution volume and renal clearance for sulfamethazine and acetylsulfamethazine did not differ significantly among the 3 phenotypes. Of special interest was the observation that rapid acetylators initially produce much greater amounts of acetyl metabolite than intermediate acetylators. The potential clinical implications of identifying rapid and intermediate acetylators are discussed in view of evidence showing that acetyl metabolites may be pharmacologically active or function as intermediates in toxic metabolic pathways.