Retrospective evaluation of the effect of omeprazole on clozapine metabolism

Mookhoek, E.J.; Loonen, Anton J. M.

doi:10.1023/b:phar.0000026808.97403.05

Cited by 21 publications

(12 citation statements)

References 5 publications

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“…The commonly used agent omeprazole is an established inducer of CYP1A2 and CYP3A4 [114]. As might be expected, lower Cps of clozapine were observed in patients who received the clozapine/omeprazole combination [115,116]. This interaction is not common to all proton pump inhibitors since replacement of omeprazole by pantaprazole resulted in increased plasma concentrations of clozapine in the non-smoker group [116], consistent with the lack of enzyme induction by pantaprazole.…”

Section: Interactions Due To Cyp1a2 Inductionmentioning

confidence: 59%

CYP-Mediated Clozapine Interactions: How Predictable Are They?

Chetty¹,

Murray

2007

CDM

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Despite the introduction of newer drugs, the atypical antipsychotic clozapine remains the most effective drug in psychotic patients who are resistant to treatment with conventional agents. Optimal therapeutic responses to clozapine have been reported with serum concentrations between 350 microg/L and 1000 microg/L. Clozapine is frequently combined with other drugs to enhance efficacy and reduce adverse reactions but pharmacokinetic interactions can have a significant impact on drug response. The majority of the interactions with clozapine are reported to be mediated by cytochrome P450 (CYP) enzymes. CYP1A2 has a major role in the oxidative metabolism of clozapine, with a minor contribution from CYP3A4, and possibly CYP2D6, CYP2C9 and CYP2C19. Interactions mediated by potent CYP1A2 inhibitors (such as fluvoxamine) or inducers (like cigarette smoke) appear to be consistent, predictable and usually clinically significant. There are many case reports of interactions between clozapine and weak CYP1A2 inhibitors or inducers which are also potent inhibitors or inducers of CYP3A4 or CYP2D6. Researchers often explain these observations on the basis of the CYP1A2 involvement. In addition, there are case reports of clinically significant interactions between clozapine and drugs that are not substrates, inhibitors or inducers of CYP1A2. These interactions are difficult to predict and may not be consistent, as reflected by the conflicting literature reports. Further research to elucidate individual differences in clozapine metabolism, with the potential to detect the dominant roles of CYPs other than CYP1A2, may assist us in predicting these interactions.

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Section: Interactions Due To Cyp1a2 Inductionmentioning

confidence: 59%

CYP-Mediated Clozapine Interactions: How Predictable Are They?

Chetty¹,

Murray

2007

CDM

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“…12 Dyspepsia and reflux may be treated with proton pump inhibitors. Although variations in clozapine concentrations have been reported with omeprazole, [16][17][18] all proton pump inhibitors are generally considered to be safe to use in patients taking clozapine.…”

Section: Gastrointestinalmentioning

confidence: 99%

Clozapine in primary care

Winckel¹,

Siskind

2017

Aust Prescr

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“…Thus, serum levels of clozapine are generally lower in smokers than in nonsmokers (Seppala et al 1999;Desai et al 2000) and in individuals who received omeprazole (Frick et al 2003;Mookhoek & Loonen 2004) or rifampicin (Wietholtz et al 1995). Removal of the inducing agent may have a pronounced effect on therapeutic control with clozapine.…”

Section: Clinically Important Atypical Antipsychotic Drugs: Clozapinementioning

confidence: 99%

Role of CYP pharmacogenetics and drug-drug interactions in the efficacy and safety of atypical and other antipsychotic agents

Murray

2006

Journal of Pharmacy and Pharmacology

106

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Cytochrome P450 (CYP) drug oxidases play a pivotal role in the elimination of antipsychotic agents, and therefore influence the toxicity and efficacy of these drugs. Factors that affect CYP function and expression have a major impact on treatment outcomes with antipsychotic agents. In particular, aspects of CYP pharmacogenetics, and the processes of CYP induction and inhibition all influence invivo rates of drug elimination. Certain CYPs that mediate the oxidation of antipsychotic drugs exhibit genetic variants that may influence in-vivo activity. Thus, single nucleotide polymorphisms (SNPs) in CYP genes have been shown to encode enzymes that have decreased drug oxidation capacity. Additionally, psychopharmacotherapy has the potential for drug-drug inhibitory interactions involving CYPs, as well as drug-mediated CYP induction. Literature evidence supports a role for CYP1A2 in the clearance of the atypical antipsychotics clozapine and olanzapine; CYP1A2 is inducible by certain drugs and environmental chemicals. Recent studies have suggested that specific CYP1A2 variants possessing individual SNPs, and possibly also SNP combinations (haplotypes), in the 5 0 -regulatory regions may respond differently to inducing chemicals. CYP2D6 is an important catalyst of the oxidation of chlorpromazine, thioridazine, risperidone and haloperidol. Certain CYP2D6 allelic variants that encode enzymes with decreased drug oxidation capacity are more common in particular ethnic groups, which may lead to adverse effects with standard doses of psychoactive drugs. Thus, genotyping may be useful for dose optimization with certain psychoactive drugs that are substrates for CYP2D6. However, genotyping for inducible CYPs is unlikely to be sufficient to direct therapy with all antipsychotic agents. In-vivo CYP phenotyping with cocktails of drug substrates may assist at the commencement of therapy, but this approach could be complicated by pharmacokinetic interactions if applied when an antipsychotic drug regimen is ongoing.

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Retrospective evaluation of the effect of omeprazole on clozapine metabolism

Abstract: Omeprazole only influenced clozapine metabolism in non-smokers. In none of the patients an adjustment of the clozapine dose was required.

Cited by 21 publications

References 5 publications

CYP-Mediated Clozapine Interactions: How Predictable Are They?

CYP-Mediated Clozapine Interactions: How Predictable Are They?

Clozapine in primary care

Role of CYP pharmacogenetics and drug-drug interactions in the efficacy and safety of atypical and other antipsychotic agents

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