ENANTIOSELECTIVE STEADY-STATE KINETICS OF UNBOUND DISOPYRAMIDE AND ITS DEALKYLATED METABOLITE IN MAN

Disopyramide is provided as a racemic mixture of R and S enantiomers, which have different pharmacodynamic and pharmacokinetic characteristics. Five volunteers were given racemic disopyramide 100 mg and 200 mg t.d.s. in a cross-over design. Plasma and urine concentrations of disopyramide and its active metabolite monodesisopropyl-disopyramide (MND) were determined at steady state by an enantioselective HPLC method. Unbound drug in plasma was measured after ultrafiltration. There was enantioselective clearance of unbound disopyramide (0.39 l.h-1.kg-1 for R-disopyramide and 0.58 l.h-1.kg-1 for S-disopyramide after 100 mg t.d.s.). The enantioselectivity was due to differences in the metabolism of disopyramide to MND and in further non-renal clearance, and the renal clearance of disopyramide was not enantioselective. The in vivo protein binding of disopyramide, which was saturable for both enantiomers, was also enantioselective. The difference in binding of the two enantiomers was explained by a difference in apparent binding capacity rather than in apparent binding affinity. The renal clearance of S-MND was significantly higher than R-MND (0.29 and 0.19 l.h-1.kg-1, respectively, after 100 mg t.d.s.). The renal clearance of MND also showed a tendency to saturation at higher concentrations.