CONCENTRATION-TIME EFFECTS ON QUINIDINE DISPOSITION KINETICS IN RHESUS-MONKEYS

Abstract

The effects of dose and duration of drug administration (time) on the disposition kinetics of quinidine [an alkaloid which is used in the management of chronic cardiac arrhythmias] were investigated in unanesthetized rhesus monkeys [Macaca mulatta]. A specific TLC-fluorometric assay was developed for the determination of quinidine in plasma, blood and urine. After the monkeys receive an i.v. bolus dose of 3-7 mg/kg, quinidine distributes rapidly in the body (T1/2.alpha. [half-life of distribution] = 2 min). The half-life associated with elimination (T1/2.beta.) was 27-35 min and primarily involved metabolic transformation. The volume of distribution varied between 0.2 and 0.65 l/kg and total clearance between 4.8 and 13 ml/min per kg. Similar estimates of T1/2.beta., clearance and volume of distribution were obtained following constant infusions producing steady-state concentrations < 6 .mu.g/ml. Prolonged infusion of quinidine at rates producing plasma concentrations in the range of 6-13 .mu.g/ml resulted in increases in the elimination half-life whereas drug clearance remained constant. An increased volume of distribution probably occurred. Both concentration and time were demonstrated to be important in producing changes in quinidine disposition kinetics. The precise mechanism underlying this phenomenon remains unanswered.