Induction of sulfamethazine acetylation by hydrocortisone in the rabbit

Abstract

Daily intravenous administration of hydrocortisone (HC) to rabbits resulted in a marked time-dependent increase in the metabolic clearance of sulfamethazine (SMZ). Kinetic analysis of the plasma concentration-time profiles for SMZ indicated that HC treatment significantly increased the rate of acetylation of SMZ without altering the renal clearances or volumes of distribution for either parent drug or the N-acetyl metabolite N-acetylsulfamethazine (NASMZ). Total body clearance of NASMZ was also unaltered. Doses of HC ranging from 25 to 150 mg/kg were equally effective in enhancing the in vivo acetylation rate of SMZ. Moreover, the induction of SMZ acetylation was reversible when treatment with the steroid was terminated. The in vitro rate of SMZ acetylation was measured in the cytosol of various organs from controls and rabbits treated with HC for 10 days. HC did not alter the Michaelis-Menten parameters for N-acetyltransferase (NAT) activity in kidney, lung, or gut. Similarly, the Km for SMZ acetylation in liver cytosol was not affected by the steroid. However, the Vmax estimates of hepatic NAT activity were significantly increased after HC treatment. At 0.5 mM SMZ and variable [acetyl-CoA], Vmax increased 3-fold from 82 +/- 20 to 244 +/- 43 mumol/min/organ, while at 0.5 mM acetyl-CoA and variable [SMZ], Vmax increased 2.8-fold from 75 +/- 19 to 208 +/- 41 mumol/min/organ. This increase was primarily due to a 69% increase in liver weight since Vmax expressed per mg of cytosolic protein was similar in both groups. The endogenous acetyl CoA concentrations were significantly increased by HC in liver and lung, but not in gut and kidney.(ABSTRACT TRUNCATED AT 250 WORDS)