FEATURES AND TOXICOKINETICS OF CLOZAPINE IN OVERDOSE

One hundred patients were commenced on clozapine in the Hunter region of Australia from July 1993 to September 1995. Of these, one ingested clozapine as a self-poisoning on two occasions. Over the same period, there were four other self-poisonings with clozapine in the region. An other case from a different region is described. The cases were identi fied from the Hunter Area Toxicology Service Database and regional psy chiatric hospitals. The severity of the poisoning is related to prior exposure and tolerance. Marked sedation at relatively low doses occurr ed in the absence of prior exposure. No reversible electrocardiographi c changes or biochemical abnormalities were demonstrated. Anticholiner gic effects were minimal, All seven cases made full recovery. A high-p ressure liquid chromatography (HPLC) method for assaying clozapine and its major metabolite, norclozapine, in plasma is described. Approxima te retention times were norclozapine, 3.8 minutes; clozapine, 5 minute s; and propyl-norclozapine, 7 minutes. The lower limit of analysis for this assay was 20 ng/ml for clozapine and the metabolite, Using the H PLC assay, serial clozapine and norclozapine plasma concentrations wer e measured in three of these cases of clozapine self poisoning. Toxico kinetic modeling was conducted by simultaneous analysis of clozapine a nd norclozapine observations. A two-compartment model with a metabolit e compartment attached to the central compartment was used. Clozapine metabolism to norclozapine was best described by linear elimination of norclozapine and nonlinear norclozapine formation. The K-m (1918 +/- 2093 mu g/l) relative to observed concentration (3396 +/- 962 mu g/l) suggests that norclozapine formation was saturated at the time of the first observation.