Clozapine toxicity in a CYP2D6 poor metaboliser: Additive effects of haloperidol and valproate on clozapine metabolism

Objective: To illustrate the complexities of clozapine metabolism with the use of therapeutic drug monitoring. Methods: We describe a case of clozapine toxicity in a patient with schizophrenia treated with the combination of clozapine, valproate and haloperidol. Results: A 24-year-old CYP2D6 poor metaboliser developed clozapine toxicity corresponding to the additive effects of haloperidol, and increasing clozapine and valproate doses. Saturation of metabolism, evidenced by a high clozapine/norclozapine ratio, was present at this time. Conclusions: Clozapine metabolism is complex and influenced by multiple factors, including interactions with hepatic P450 enzyme inducers/inhibitors, genetic polymorphisms and the potential for saturation of the N-demethylation metabolic pathway.

Cardiovascular and neurological toxicity of venlafaxine

1 We report a case of venlafaxine overdose and describe pharmacokinetic data on drug disposition. 2 Case report. Serial venlafaxine levels were measured and drug half-life calculated and compared to data at therapeutic concentrations. Metabolite concentrations were also measured and the potential for toxicity described with reference to individual variation in such metabolism 3 Venlafaxine can cause significant cardiac and neurotoxicity. Its potential for causing such toxicity may be dependent on whether an individual has the extensive metaboliser cytochrome CYP2D6 phenotype or the poor metaboliser phenotype