Disposition kinetics of disopyramide in human healthy volunteers described by an open three compartment model

Disposition kinetics of disopyramide was examined in an open randomised cross-over study in 8 healthy volunteers. Disopyramide was randomly administered as a single bolus injection (150 mg) over a period of 5 min. and as an infusion (28.2) mg/h to steady state. Disposition kinetics of disopyramide were most precisely described by an open three compartment model according to Akaike's information criteria. Significant positive correlations (0.909 +/- 0.04, P less than 0.05 (injection study); 0.787 +/- 0.11, P less than 0.05 (infusion study] were observed between total serum concentrations of disopyramide and renal clearance while no significant correlation could be demonstrated between free serum concentrations and renal clearance. This implies a constant value of unbound renal clearance. The results are consistent with non linear kinetics (mainly caused by the variable free fraction of the drug), when based on total serum concentrations. The disposition of unbound disopyramide, however seems to be linear (i.e. the kinetic parameters are independent of dose) in the bolus injection study. Total elimination clearance (free and total), volume of distribution and elimination half-life were significantly higher in the steady state experiment than in the bolus injection study.