Biotransformation of Post-Clozapine Antipsychotics

  title={Biotransformation of Post-Clozapine Antipsychotics},
  author={Silvio Caccia},
  journal={Clinical Pharmacokinetics},
  • S. Caccia
  • Published 1 May 2000
  • Psychology, Medicine
  • Clinical Pharmacokinetics
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… 

Cytochrome P450 polymorphisms and response to antipsychotic therapy.

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Optimal plasma concentration ranges are proposed for clozapine, risperidone, paliperidone and olanzapine because the studies of quetiapine and amisulpride provide only limited information and there is no direct evidence concerning ziprasid one, aripiprazole, sertindole, brexpiprazoles and cariprazine.

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This review of the literature concerning the relationships between plasma concentrations of SGAs and clinical responses is divided by dividing the studies on the basis of the length of their observation periods by indicating a relationship between clinical outcomes and plasma concentrations.

Cytochrome P450 Phenotyping/Genotyping in Patients Receiving Antipsychotics

  • M. Dahl
  • Psychology, Medicine
    Clinical pharmacokinetics
  • 2002
The current rapid developments in molecular genetic methodology and pharmacogenetic knowledge can in the near future be expected to provide new tools for prediction of the activity of the various drugmetabolising enzymes.

Fatalities Associated with Therapeutic Use and Overdose of Atypical Antipsychotics

Since 1989, several novel antipsychotic drugs have become available for use including clozapine, risperidone, olanzapine, quetiapine and ziprasidone. These agents represent a substantial improvement

Iloperidone: a new benzisoxazole atypical antipsychotic drug. Is it novel enough to impact the crowded atypical antipsychotic market?

In order to introduce iloperidone as an agent for the treatment of schizophrenia, a short overview of the disease and of the most important antipsychotic drugs available or under development will be reported.

Metabolism of Psychotropic Drugs

In this chapter, specific metabolism of antidepressant and antipsychotic drugs is presented for the main CYP enzymes CYP2D6, CyP2C19, CYP 2C9, and CYP1A2 and the impact of genetic polymorphisms in these enzymes is pointed out.

CYP2D6 Genotyping and Antipsychotic-Associated Extrapyramidal Adverse Effects in a Randomized Trial of Aripiprazole Versus Quetiapine Extended Release in Children and Adolescents, Aged 12–17 Years, With First Episode Psychosis

The results do not support routine use of CYP2D6 testing as a predictor of drug-induced parkinsonism or akathisia risk in clinical settings and further studies with larger samples of CYD6 poor metabolizers are needed.



Drug metabolism and atypical antipsychotics

The emerging role of cytochrome P450 3A in psychopharmacology.

Knowing the substrates, inhibitors, and inducers of CYP3A3/ and other cytochrome P450 isoforms may help clinicians to anticipate and avoid pharmacokinetic drug interactions and improve rational prescribing practices.

Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4

The formation of 9-Hydroxyrisperidone is highly correlated with testosterone 6β-hydroxylase activities, suggesting that inducible CYP3A contributes significantly to the metabolism of ris peridone in rat.

Metabolism of the Newer Antidepressants

  • S. Caccia
  • Biology, Medicine
    Clinical pharmacokinetics
  • 1998
Several chemically unrelated agents has been developed and introduced in the past decade, to supplement the earlier antidepressants, as well as drugs with distinct neurochemical profiles such as mirtazapine, nefazodone, moclobemide and tianeptine, which may explain the individual variability with all these drugs.

The Metabolism of Atypical Antipsychotic Drugs: An Update

  • W. Shen
  • Psychology, Medicine
    Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists
  • 1999
None of all six atypical antipsychotic drugs are identified as significant inhibitors or inducers to any co-administered medication, and the need for more research to address some pertinent clinical issues in the metabolism of those drugs is suggested.

Polymorphic Drug Oxidation

The high incidence of PM (and of heterozygous extensive metabolisers) of S-mephenytoin in Asia might be the reason for the reported higher sensitivity of Orientals to diazepam compared with Caucasians.

A pharmacological, pharmacokinetic and clinical overview of risperidone, a new antipsychotic that blocks serotonin 5‐HT2 and dopamine D2 receptors

The clinical success of risperidone suggests that the development of compounds with selective affinity for 5-HT2 or other serotonin receptors may result in even further improvements in the pharmacotherapy of psychiatric disorders.

In vitro interaction of the antipsychotic agent olanzapine with human cytochromes P450 CYP2C9, CYP2C19, CYP2D6 and CYP3A.

In all cases, the calculated percent inhibition of these cytochromes P450 by olanzapine was < 0.3%, suggesting that there would be little in vivo inhibition of the metabolism of substrates of these enzymes when co-administered with olanZapine.

New antipsychotics: the present status

According to this classification the new antipsychotics can be subdivided into three main categories: the relatively pure dopamine antagonists; the dopamine (D2)-serotonin (5-HT2)-norepinephrine (α1 ) antagonists (risperidone, ziprazidone and sertindole); and the multireceptor antagonists (clozapine, olanzapine and seroquel).

Pharmacokinetics and drug interactions: update for new antipsychotics.

  • L. Ereshefsky
  • Medicine, Psychology
    The Journal of clinical psychiatry
  • 1996
Clozapine, the archetypal atypical agent, has a complex pharmacokinetic profile with extremely large interpatient variability and many well-documented drug-drug interactions, which presents special challenges in dose optimization and requires vigilant clinical monitoring for cardiovascular, neurologic, and hematologic adverse effects.