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Features and Toxicokinetics of Clozapine in Overdose

Reith, David*; Monteleone, Jonathan P. R.; Whyte, Ian M.; Ebelling, William§; Holford, Nicholas H. G.; Carter, Gregory L.**

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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. Another case from a different region is described. The cases were identified from the Hunter Area Toxicology Service Database and regional psychiatric hospitals. The severity of the poisoning is related to prior exposure and tolerance. Marked sedation at relatively low doses occurred in the absence of prior exposure. No reversible electrocardiographic changes or biochemical abnormalities were demonstrated. Anticholinergic effects were minimal. All seven cases made full recovery. A high-pressure liquid chromatography (HPLC) method for assaying clozapine and its major metabolite, norclozapine, in plasma is described. Approximate retention times were norclozapine, 3.8 minutes; clozapine, 5 minutes; and propyl-norclozapine, 7 minutes. The lower limit of analysis for this assay was 20 ng/ml for clozapine and the metabolite. Using the HPLC assay, serial clozapine and norclozapine plasma concentrations were measured in three of these cases of clozapine self poisoning. Toxicokinetic modeling was conducted by simultaneous analysis of clozapine and norclozapine observations. A two-compartment model with a metabolite 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 Km (1918 ± 2093 µg/l) relative to observed concentration (3396 ± 962 µg/l) suggests that norclozapine formation was saturated at the time of the first observation.

*Royal Children's Hospital, Herston, Queensland, Australia,†Department of Pharmacology and Clinical Pharmacology, School of Medicine, University of Auckland, Auckland, New Zealand, ‡Department of Clinical Toxicology and Pharmacology, Newcastle Mater Misericordiae Hospital, New South Wales, §Division of Clinical Chemistry, Hunter Area Pathology Service, Newcastle, New South Wales, **Department of Liaison Psychiatry, Newcastle Mater Misericordiae Hospital, New South Wales, Australia

Received July 31, 1996; accepted September 4, 1997.

Address correspondence and reprint requests to Ian M. Whyte, Department of Clinical Toxicology and Pharmacology, Newcastle Mater Misericordiae Hospital, Locked Bag 7, Hunter Regional Mail Centre, New South Wales, Australia 2310.

Hunter Area Toxicology Service, Newcastle Mater Misericordiae Hospital, New South Wales, Australia.

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