Concentration-time effects of quinidine disposition kinetics in rhesus monkeys

The effects of dose and duration of drug administration (time) on the disposition kinetics of quinidine were investigated in unanesthetized rhesus monkeys. A specific thin-layer chromatography-fluorometric assay was developed for the determination of quinidine in plasma, blood and urine. After the monkeys receive an i.v. bolus dose of 3 to 7 mg/kg, quinidine distributes rapidly in the body (T 1/2alpha = 2 minutes). The half-life associated with elimination (T 1/2 beta) was 27 to 35 minutes and primarily involved metabolic transformation. The volume of distribution varied between 0.2 and 0.65 liters/kg and total clearance between 4.8 and 13 ml/min/kg. Similar estimates of T 1/2 beta, clearance and volume of distribution were obtained following constant infusions producing steady-state concentrations less than 6 microng/ml. Prolonged infusion of quinidine at rates producing plasma concentrations in the range of 6 to 13 microng/ml resulted in increases in the elimination half-life whereas drug clearance remained constant. This observation suggests an increased volume of distribution. Both concentration and time were demonstrated to be important in producing changes in quinidine disposition kinetics. The precise mechanism underlying this phenomenon remains unanswered.