Kinetic analysis of myocardial uptake and negative inotropic effect of amiodarone in rat heart

The distribution kinetics of the highly lipophilic antiarrhythmic agent amiodarone is not well understood. The purpose of the present investigation was to develop a pharmacokinetic–pharmacodynamic (PK/PD) model to describe cardiac uptake and the negative inotropic effect of amiodarone in the isolated perfused rat heart. Amiodarone (10 μM) was infused for 15 min to 6 hearts. The time course of outflow concentration and left ventricular developed pressure were measured and analyzed by the model. The uptake of amiodarone by the heart was flow limited and characterized by an extremely high partition coefficient with a predicted tissue washout half-live of 17 h. Only 36.8% of input amount to heart recovered within 45 min after start of the 15 min infusion. The negative inotropic effect was delayed with a time constant of 11 min and the maximal decrease in left ventricular developed pressure was described by a sigmoid Emax model with an Emax of 37.7% and an EC50 of 0.53 μM. Our results suggest a rapid tissue uptake and a moderate negative inotropic effect of amiodarone after intravenous injection.