Time-dependent, plasma-sulfate-independent kinetics of salicylamide in dogs

The mechanisms of the dose-dependent elimination kinetics of salicylamide in dogs were examined. Salicylamide was infused continuously over three consecutive 90-min periods. The rates of infusion during Periods I and III were the same. During Period II the infusion rate was 2.5-fold higher. Plasma concentrations of inorganic sulfate were kept constant by the administration of exogenous sulfate. The plasma concentrations of salicylamide, which reached steady state during Period I but not during II or III, were twice as high at the end of Period III than those at the end of Period I. Typical Michaelis-Menten kinetics do not explain these results. When salicylamide was given as 40 mg/kg single oral dose, clearance of an intravenous tracer dose of radiolabeled salicylamide was greatly reduced within 10 min but returned to baseline values by 240 min after the oral dose, despite persistently low plasma concentrations of inorganic sulfate. Therefore, dose- and time-dependent factors other than Michaelis-Menten kinetics, depletion of inorganic sulfate concentrations, and rate limitation of supply of "active sulfate" from plasma inorganic sulfate stores produce the dose- and time-dependent kinetics of salicylamide in the dog. Product inhibition of salicylamide sulfoconjugation remains a possible explanation.