norclozapine and Drug-Overdose

A 40-year-old schizophrenic man was found unconscious, with constricted pupils, sinus tachycardia, and twitching of the limbs. There were signs of lung infection, which was treated with antibiotics, and mild rhabdomyolysis. He regained consciousness over 8 hours, and reported taking 3-4 g clozapine. Recovery was uneventful. Measured peak clozapine and norclozapine concentrations were 3.53 mg/L and 0.70 mg/L, respectively. The concentration-time curves were biphasic, with secondary peaks at approximately 36 hours postadmission. Terminal elimination half-lives were 16.9 hours and 22.5 hours for clozapine and norclozapine, respectively.. Clozapine and its metabolite norclozapine can show biphasic plasma concentration-time curves after overdosage.

Topics: Acute Disease; Adult; Antipsychotic Agents; Chromatography, High Pressure Liquid; Clozapine; Drug Overdose; Half-Life; Humans; Male

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 micrograms/l) relative to observed concentration (3396 +/- 962 micrograms/l) suggests that norclozapine formation was saturated at the time of the first observation.

Topics: Adult; Antipsychotic Agents; Australia; Chromatography, High Pressure Liquid; Clozapine; Drug Overdose; Female; Humans; Male; Middle Aged; Suicide, Attempted

The neuroleptic drug clozapine is used in the treatment of schizophrenia and is characterized by not having the extrapyramidal side-effects usually shown by neuroleptics. Unfortunately clozapine has other side-effects, which limit its use. This study presents methods for the analysis of clozapine and desmethylclozapine in whole blood and tissue. Case histories and pathology findings are described for 3 autopsy cases with fatal concentrations of clozapine, 5 with toxic concentrations and 2 with therapeutic concentrations together with the concentrations found in a living person.

Topics: Adult; Chromatography, Gas; Chromatography, High Pressure Liquid; Clozapine; Drug Overdose; Fatal Outcome; Female; Forensic Medicine; Humans; Liver; Male; Middle Aged; Muscles; Suicide

Toxicological analyses are often performed to investigate suspected poisoning, but the interpretation of results may not be straightforward. We studied suspected poisoning cases 1992-2003 where blood clozapine and N-desmethylclozapine (norclozapine) were measured in order to assess the relationship of these parameters to outcome.. Samples were referred from clinicians, pathologists/coroners, or via the Clozaril Patient Monitoring Service (CPMS, Novartis). Information was gathered from clinical, post-mortem, or coroners' reports.. There were seven fatal [five male, two female; median (range) age 28 (24-41) year] and five non-fatal [four male, one female; median age 35 (26-41) year] clozapine overdoses. The median post-mortem blood clozapine and norclozapine concentrations were 8.2 (3.7-12) and 1.9 (1.4-2.4)mg/L, respectively [median clozapine:norclozapine ratio 4.4 (2.9-5.1)]. The median plasma clozapine and norclozapine concentrations (first or only sample) were 3.9 (1.7-7.0) and 0.40 (0.30-0.70)mg/L, respectively [median clozapine:norclozapine ratio 7.6 (5.3-18)] in the remainder. These overdoses were in patients who were poorly or non-adherent to clozapine, or who had taken tablets prescribed for someone else. In 54 further people who died whilst receiving clozapine [38 male, 16 female; median age 41 (22-70) year], the median post-mortem blood clozapine and norclozapine concentrations were 1.9 (0-7.7, n = 43) and 1.4 (0-6.0, n = 39)mg/L, respectively [median clozapine:norclozapine ratio 1.5 (0.4-7.6, n = 38)]. The median post-mortem increase in blood clozapine and norclozapine as compared to the most recent ante-mortem measurement was 489 (98-5,350)% and 371 (139-831)%, respectively [median sample time before death 14 (0-30, n = 21) days].. Clozapine poisoning cannot be diagnosed on the basis of blood clozapine and norclozapine concentrations alone. The analysis of ante-mortem blood specimens collected originally for white cell count monitoring and the blood clozapine:norclozapine ratio may provide additional interpretative information.

Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Drug Overdose; Female; Forensic Medicine; Humans; Leukocyte Count; Male; Middle Aged; Poisoning; Postmortem Changes; Suicide; Treatment Refusal; United Kingdom

Massive drug overdoses provide a unique opportunity to observe human pharmacokinetic data not otherwise ethically available. They can also provide practical examples for teaching thoughtful application of the principles of clinical pharmacology. Following a case of clozapine overdose in which onset of toxicity was delayed by 72 hours, a probable explanation was found in an exploration of three cases with unusual concentration-time profiles and revealed unexpected implications for the management of clozapine overdoses. The authors systematically addressed the possible mechanisms proposed in the literature for an unusual plateau in concentrations observed in three clozapine overdoses. The effects that the most commonly suggested explanations (i.e., delayed absorption and saturated or impaired metabolism) would have on both clozapine and norclozapine concentrations were then modeled using the data available from those three cases to provide an objective illustration for comparison. This exercise was then used as a teaching seminar, leading students through the steps required to reach a logical explanation for the observed delayed toxicity and to consider the implications for therapy. Delayed absorption best predicted the sustained serum clozapine and norclozapine concentrations observed in three cases, and modeling suggests that much of the drug remains in the gut, available for absorption for days following an overdose. As a seminar, the exercise provides students with a practical example of the value of systematically ruling out possible explanations by considering what effects various pharmacokinetic alterations would have on observed data. Absorption following massive clozapine overdose appears fundamentally different from that with conventional dosing. This suggests a potential for delayed or prolonged toxicity, extending well beyond the time frame predicted by its half-life, unless aggressive and sustained efforts are applied to remove clozapine from the gut. Data from drug overdoses provide opportunities to explore unusual aspects of pharmacokinetics, better understand future overdoses of the same agent, and present excellent material for teaching. A seminar illustrating the role that thoughtful application of pharmacologic principles had in addressing this case is now used to introduce the clinical aspects of pharmacology to students at our institutions.

Topics: Adult; Aged; Clozapine; Drug Overdose; Female; Half-Life; Humans; Male; Metabolic Clearance Rate; Pharmacology, Clinical; Problem-Based Learning; Serotonin Antagonists; Teaching