Myocardial pharmacokinetics of amitriptyline and clomipramine in the isolated, perfused rabbit heart

The myocardial pharmacokinetics of amitriptyline and clomipramine were investigated in isolated rabbit hearts, which were perfused with a modified Krebs-Henseleit solution containing the equimolar concentrations 0.25 or 0.28 micrograms ml-1 of the compounds, respectively. The rate of myocardial uptake of the drugs as a function of time was indirectly followed by determinations of the concentrations of the compounds in fractional samples of the coronary output of perfusate. The time course of disposition of amitriptyline from the myocardium was similarly followed after changing from amitriptyline perfusion to perfusion with drug-free liquid. The amitriptyline accumulation and disposition processes were found to fit bi-exponential functions indicating myocardial two-compartment characteristics of the compound. Clomipramine did only exhibit one-compartment myocardial characteristics. The biological half-life of amitriptyline in the myocardium was about 37.7 min. and a pronounced cardiac accumulation of about 340 micrograms of the compound at steady state was evidenced. The myocardial half-life of clomipramine was about 106 min. and the accumulated amount at steady state was calculated to be 1055 micrograms. After amitriptyline perfusion an increase in the pharmacokinetic rate constants k10 and k12 and a decrease in the apparent central volume of distribution was observed.