Stereoselective pharmacokinetics of disopyramide enantiomers in man

The plasma protein binding and pharmacokinetics of S(+)-disopyramide and R(-)-disopyramide following infusions of 100 mg were compared in five healthy human volunteers. The binding of S(+)-disopyramide was higher than that of R(-)-disopyramide at similar unbound concentrations in all subjects. The association constant characterizing the interaction between plasma protein and the S(+)- and R(-)-enantiomers was 17.1 X 10(5) M-1, and 7.68 X respectively. The unbound clearance and half-life of S(+)-disopyramide averaged 604 ml/min and 3.67 hr, respectively, and differed from that of R(-)-disopyramide, which averaged 401 ml/min and 4.62 hr, respectively. Both enantiomers appear to undergo active tubular secretion. The unbound renal clearance of the S(+)- and R(-)-enantiomers averaged 338 and 182 ml/min, respectively (p = 0.05). The unbound steady-state volume of distribution of S(+)- and R(-)-disopyramide averaged 172 and 141 liters, respectively (p = 0.14). The renal clearance of the mono-N-dealkylated metabolite of disopyramide following the administration of S(+)- and R(-)-disopyramide averaged 345 and 170 ml/min, respectively (p less than 0.05).