Biotransformation of Post-Clozapine Antipsychotics

Abstract

The need to develop new antipsychotics that have fewer motor adverse effects and offer better treatment of negative symptoms has led to a new generation of drugs. Most of these drugs undergo extensive first-pass metabolism and are cleared almost exclusively by metabolism, except for amisulpride whose clearance is largely due to urinary excretion. Risperidone has metabolic routes in common with ziprasidone but shows differences in regard to other main pathways: the benzisoxazole moiety of risperidone is oxidised by cytochrome P450 (CYP) 2D6 to the active 9-hydroxyrisperidone, whereas the benzisothiazole of ziprasidone is primarily oxidised by CYP3A4, yielding sulfoxide and sulfone derivatives with low affinity for target receptors in vitro. Olanzapine, quetiapine and zotepine also have some common metabolic features. However, for the thienobenzodiazepine olanzapine a main metabolic route is direct conjugation at the benzodiazepine nucleus, whereas for the dibenzothiazepine quetiapine and the dibenzothiepine zotepine it is CYP3A4-mediated oxidation, leading to sulfoxidation, hydroxylation 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 routes with the structurally related available drugs, they too have pharmacologically 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 concentrations of the parent drug or its metabolite(s), but we know very little about others (e.g. amisulpride isomers, nemonapride). For yet others, information is scarce about the activity of the main metabolites and whether and how these contribute to the effect of the parent drug. Aging reduces the clearance of most antipsychotics, except amisulpride (which requires further evaluation) and ziprasidone. Liver impairment has little or no effect on the pharmacokinetics of olanzapine, quetiapine, risperidone (and 9-hydroxy-risperidone) and ziprasidone, but information is lacking for amisulpride. Renal impairment significantly reduces the clearance and prolongs the elimination half-life of amisulpride and risperidone. Again, studies are still not available for some drugs (zotepine) and have focused on the parent drug for others (olanzapine, quetiapine, ziprasidone) despite the fact that renal impairment would be expected to lower the clearance of more polar metabolites. Addressing these issues may assist clinicians in the design of safe and effective regimens for this group of drugs, and in selecting the best agent for each specific population.

Plasma amisulpride levels in schizophrenia or schizoaffective disorder

“…In in vitro studies, no inhibition of cytochrome P450 isozyme by amisulpride could be seen (Gillet et al, 2000). However, the details of its interactions with cytochrome P450 isozymes have not been fully elucidated and, most importantly, clinical studies on this issue are lacking (Caccia, 2000).…”

“…Caccia, 2000) and whether there is any correlation with clinical effectiveness in patients at various oral doses.…”

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

“…Data on the in vitro biotransformation of antidepressants and antipsychotics have been reviewed elsewhere. [8][9][10][11][12] Studies were restricted to those providing data on effects of genetic polymorphisms in CYP2D6, CYP2C19, or CYP2C9. The functional impact of other polymorphisms in drug-metabolizing enzymes including CYP1A2, CYP2A6, CYP2B6, CYP3A4, -5, and -7 or phase-II enzymes in psychopharmacology was considered to be either too moderate or controversial.…”

“…CYP3A4 is the main enzyme involved in the metabolism of bromperidole, iloperidone, perospirone, quetiapine, and ziprasidone. 8,44 For chlorpromazine, remoxipride, and sertindole, only in vitro data exist on involvement of CYP2D6. 8 Remoxipride and sertindole were withdrawn from the market due to adverse drug reactions (aplastic anemia and arrhythmia).…”

“…8,44 For chlorpromazine, remoxipride, and sertindole, only in vitro data exist on involvement of CYP2D6. 8 Remoxipride and sertindole were withdrawn from the market due to adverse drug reactions (aplastic anemia and arrhythmia). Melperone is described as potent inhibitor of CYP2D6 but studies on impact of CYP2D6 polymorphisms on melperone metabolism are not yet available.…”