Dose-dependent pharmacokinetic profile of silvex following intravenous administration in rats

The pharmacokinetic profile of silvex was defined in rats after single intravenous doses of 5 and 50 mg/kg 14C ring-labeles silvex. Clearance of silvex from plasma at the 5 mg/kg dose was linear with a half-life of 16.2 hr, while clearance at the 50 mg/kg dose was nonlinear. Activities of 14C recovered in excreta were 94.1 and 95.1% of the administered doses at 5 and 50 mg/kg, respectively. Excreta was collected for 192 hr at 5 mg/kg and 216 hr at 50 mg/kg. Urinary excretion of 14C activity accounted for 80.5 and 68.7% of the administered dose at 5 and 50 mg/kg, respectively; fecal excretion accounted for 13.7 and 26.4% of the administered dose at 5 and 50 mg/kg, respectively. Urinary excretion of silvex is saturated at the 50 mg/kg dose. Significant amounts of silvex are excreted in bile and undergo enterohepatic circulation. Concentrations of silvex in liver and kidney are higher than those in fat, brain, and muscle 8 and 216 hr after administration. In a companion oral study, silvex was extensively if not completely absorbed. The pharmacokinetic data presented indicate that statistical projection of experimental results with large doses of silvex to predict the hazard of exposure to small amounts is not justified because the capability to excrete silvex in urine has been saturated.