MODELING OF NONLINEAR PHARMACOKINETICS IN SHEEP AFTER SHORT-TERM INFUSION OF CARDIOTOXIC DOSES OF IMIPRAMINE

Imipramine was administered to sheep (n=10) by intravenous infusion in high doses (450 mg-900 mg) to elicit cardiovascular shock. A cardiac assist device was then employed to manage the acute overdose situation . The concentration-time course of imipramine and its metabolite desme thylimipramine in plasma was measured by HPLC. As an indicator of imip ramine's cardiotoxic effect, cardiac output was monitored. The aim of the study was to evaluate the pharmacokinetics under these conditions and to assess the efficiency of a cardiac assist device with (n=5) and without (n=5) an integrated haemoperfusion unit in removing drug from the circulation. The kinetics of imipramine could be described by a t hree compartment body model with concentration-dependent clearance res ulting in non-linear kinetics. The changes in cardiac output with time could be linked to the pharmacokinetic model by a linear relationship . The cardiac assist device was found to contribute to the overall eli mination of imipramine whereas the haemoperfusion unit had no clinical ly relevant impact.