Sulfamethazine as a model compound to assess sex hormone-dependent cytochrome P-450 activity in rats

Plasma disposition and urinary recovery of sulfamethazine (SMZ), its N4-acetylated metabolite (N4AcSMZ), and two of its hydroxylated metabolites [5-hydroxysulfamethazine (5OHSMZ) and 6-hydroxymethylsulfamethazine (6CH2OHSMZ)] were determined in male and female rats, in castrated males, and in rats pretreated with various steroid hormones. Male rats had a 2-fold higher SMZ plasma clearance than females, castrates, and males treated with flutamide (a testosterone antagonist). When castrated male rats were treated with testosterone or trenbolone, SMZ plasma clearance returned to normal values. Higher SMZ plasma clearance rates in the presence of androgens went together with higher urinary recoveries of the 6CH2OHSMZ metabolite. In hepatic microsomes of male rats lower apparent KM values, and higher Vmax values for 6CH2OHSMZ and 5OHSMZ formation were found than in microsomes of female rats. Castration or treatment of male rats with flutamide markedly reduced microsomal SMZ hydroxylation rates. Pretreatment of male or female rats with phenobarbital or triacetyl-oleandomycin had no effect on microsomal SMZ hydroxylation, whereas a continuous infusion with bovine somatotropin in male rats caused a marked decrease in SMZ hydroxylation rate. Finally, SMZ hydroxylation to 6CH2OHSMZ and 5OHSMZ in hepatic microsomes from male rats was strongly inhibited by monoclonal antibodies against P-4502C11. These results suggest that the male-specific P-4502C11 enzyme plays an important role in the hydroxylation of SMZ to 6CH2OHSMZ and 5OHSMZ in rats. SMZ seems a useful model compound to assess hormone effects on oxidative biotransformation (in vivo and in vitro) in rats.