Biotransformation of post-clozapine antipsychotics - Pharmacological implications

The need to develop new antipsychotics that have fewer motor adverse effect s and offer better treatment of negative symptoms has led to a new generati on of drugs. Most of these drugs undergo extensive first-pass metabolism an d are cleared almost exclusively by metabolism, except for amisulpride whos e clearance is largely due to urinary excretion. Risperidone has metabolic routes in common with ziprasidone but shows diffe rences in regard to other main pathways: the benzisoxazole moiety of risper idone is oxidised by cytochrome P450 (CYP) 2D6 to the active 9-hydroxyrispe ridone, whereas the benzisothiazole of ziprasidone is primarily oxidised by CYP3A4, yielding sulfoxide and sulfone derivatives with low affinity for t arget receptors in vitro. Olanzapine, quetiapine and zotepine also have som e common metabolic features. However, for the thienobenzodiazepine olanzapi ne a main metabolic route is direct conjugation at the benzodiazepine nucle us, whereas for the dibenzothiazepine quetiapine and the dibenzothiepine zo tepine iris CYP3A4-mediated oxidation, leading to sulfoxidation, hydroxylat ion and dealkylation for quetiapine, but N-demethylation to the active nor- derivative for zotepine. Although the promising benzisoxazole (iloperidone) and benzisothiazole (perospirone) antipsychotics share some metabolic rout es with the structurally related available drugs, they too have pharmacolog ically relevant compound-specific pathways. For some of the new antipsychotics we know the isoenzymes involved in their main metabolic pathways and the endogenous and exogenous factors that, by affecting enzyme activity, can potentially modify steady-state concentratio ns of the parent drug or its metabolite(s), but we know very little about o thers (e.g. amisulpride isomers, nemonapride). For yet others, information is scarce about the activity of the main metabolites and whether and how th ese contribute to the effect of the parent drug. Aging reduces the clearance of most antipsychotics, except amisulpride (whi ch requires further evaluation) and ziprasidone. Liver impairment has littl e or no effect on the pharmacokinetics of olanzapine, quetiapine, risperido ne (and 9-hydroxy-risperidone) and ziprasidone, but information is lacking for amisulpride. Renal impairment significantly reduces the clearance and p rolongs the elimination half-life of amisulpride and risperidone. Again, st udies are still not available for some drugs (zotepine) and have focused on the parent drug for others (olanzapine, quetiapine, ziprasidone) despite t he fact that renal impairment would be expected to lower the clearance of m ore polar metabolites. Addressing these issues may assist clinicians in the design of safe and eff ective regimens for this group of drugs, and in selecting the best agent fo r each specific population.