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 desmethylimipramine in plasma was measured by HPLC. As an indicator of imipramine'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 three compartment body model with concentration-dependent clearance resulting 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 elimination of imipramine whereas the haemoperfusion unit had no clinically relevant impact.The tricyclic antidepressant imipramine has several different actions at different concentrations (Reisby et al. 1977;Preskorn 1989). The main use of the compound is as an antidepressant in major depressive disorders. In this indication effective therapeutic concentrations of imipramine plus its active metabolite desmethylimipramine above 500-700 nmol/l (1 58-222 p g / d imipramine) are reported (Brarsen et al. 1986). However, concentrations of imipramine plus desmethylimipramine above 1400 nmoln (444 pg/ ml imipramine) are associated with an increased incidence of serious cardiac and central nervous side effects which can be life-threatening. Therefore much work has been devoted to the task of investigating the clinical pharmacokinetics of imipramine and its metabolites (Sallee & Pollock 1990;Petit et al. 1977) as well as of finding ways and means to manage tricyclic antidepressant overdose (Heath et al. 1982; Marshall & Forker 1982 diovascular effects of tricyclic antidepressants in the range of therapeutic concentrations. Especially imipramine shows in addition antiarrhythmic activity (Glassman 1984). A thorough understanding of the pharmacokinetics of tricyclic antidepressants in a high-concentration situation is required in order to devise techniques and procedures for the control of critical cases. The only conceivable way to investigate the pharmacokinetics and pharmacodynamics of a drug in the situation of toxic concentrations under controlled study conditions is to use animal models. Hence, we have investigated the pharmacokinetics and the cardiovascular effects of imipramine in a sheep model. Concentration-time profiles and cardiac function parameters were recorded in a situation resembling acute overdose in all aspects including the use of a mechanical cardiac assist device. Materials and MethodsClinical methods. Ten female adult sheep (mean body weight 68 kg, range 42 to 104 kg) were included in the study. Animals were anaesthetized with t...

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We have developed an implantable venous catheter for repeated blood sampling in the Munich minipig. The catheter consists of silicone tubing, with a polyesterfibre net for fixation in the subcutaneous tissue of the neck. It was introduced into the right jugular vein, and its tip was positioned in the right atrium. The extravascular part of the catheter was tunnelled subcutaneously to the exit point in the subscapular region. In order to avoid contamination of the silicone tubing by drugs, intravenous administrations were performed via a second polyethylene catheter inserted into the implanted catheter. In 9 minipigs, the catheter remained patent for an average of 200 days (maximum 515 days). The animals did not show any signs of discomfort or impaired health.