The effect of phenobarbital and SKF 525A on tocainide pharmacokinetics in the rat

Studies were carried out to determine the susceptibility of tocainide disposition to the induction and inhibition of drug metabolizing enzymes by using the rat as an animal model. Pretreatment with phenobarbital resulted in a significant reduction in the area under the plasma concentration vs. time curve of tocainide administered i.v. An increase in clearance due to phenobarbital treatment was mainly accounted for by the increase in the disposition rate constant of tocainide. After p.o. or i.v. administration of tocainide, a significant reduction in the percentage of dose excreted as intact drug in the urine was observed in test animals. SKF 525A pretreatment resulted in impairment of the elimination of tocainide as reflected by a reduction in clearance mainly due to a decrease in the disposition rate constant. The inhibition of tocainide metabolism was apparent from the greater than 100% increase in the amount of intact drug excreted in the urine. The differential extent of inhibition of tocainide metabolism observed after a 15 and 20 mg/kg dose supports the involvement of metabolic processes in the nonlinear elimination kinetics of tocainide.