Imipramine and 2-hydroxyimipramine: comparative cardiotoxicity and pharmacokinetics in swine

The hemodynamic, cardiographic, and initial pharmacokinetic characteristics of the de novo administration of the 2-hydroxymetabolite (2-OH-IMI) of imipramine (IMI), compared with its parent was studied in a swine preparation. Cardiac output, arterial pressure, and the continuous electrocardiogram were assessed after the intravenous administration of the drug or its metabolite. Plasma, sampled over 120 min and CSF sampled at 60 min were analyzed by reverse phase HPLC with spectroflurometric detection. Equilibrium dialyses were performed on plasma sampled at 60 min. 2-OH-IMI, in doses of 5-6 mg/kg, compared to dosages of IMI up to 8.5 mg/kg, produced a significantly greater incidence of life-threatening arrhythmias, and caused profound and significant decreases in blood pressure and cardiac output. 2-OH-IMI had a smaller volume of distribution (Vd) and shorter half-life. CNS penetration, as estimated by CSF/plasma ratios, was significantly greater for 2-OH-IMI. These phenomena were partly accounted for by significantly less protein binding for the hydroxymetabolite. It is concluded that 2-OH-IMI has increased penetrance into the CNS despite a smaller Vd and that it is significantly more cardiotoxic than its parent.