Dose-dependent kinetics of quinidine in the perfused rat liver preparation. Kinetics of formation of active metabolites.

The disposition of quinidine and the kinetics of metabolite formation were studied in the once-through perfused rat liver preparation by the stepwise increase in quinidine concentration. Dose-dependent kinetics of quinidine were observed; the steady-state hepatic extraction ratio decreased from 0.97 to 0.37 when input quinidine concentration varied from 1.34 to 33.9 micrograms/ml. Moreover, the formation of 3-hydroxyquinidine (detected only in perfusate as unconjugated 3-hydroxyquinidine) remained relatively linear while the formation of O-desmethylquinidine (present in bile and perfusate mostly as conjugates) apparently approached saturation kinetics within the quinidine concentrations used. The dose-dependent character of quinidine elimination cannot be attributed to changes in drug binding, as the blood/plasma ratio (4.07) and the degree of drug unbound in plasma (66.5%) remained unaltered for the quinidine concentrations used.