Case Studies of Adjunctive Agents in Clozapine-Resistant Schizophrenic Patients

Kontaxakis, V.P.; Ferentinos, Panagiotis; Havaki-Kontaxaki, B.J.; Paplos, K.G.; Roukas, Dimitrios; Christodoulou, George N.

doi:10.1097/01.wnf.0000154222.37887.a8

Cited by 17 publications

(7 citation statements)

References 28 publications

(49 reference statements)

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“…The clinical efficacy of CLZ has been improved in certain patients by coadministration of fluvoxamine (Ozdemir et al, 2001;Kontaxakis et al, 2005). Thus, Ozdemir et al (2001) reported a patient who, despite receiving a dose of CLZ that was close to the upper recommended limit, had only subtherapeutic serum concentrations of the drug.…”

Section: Discussionmentioning

confidence: 99%

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Interindividual Variation in Relative CYP1A2/3A4 Phenotype Influences Susceptibility of Clozapine Oxidation to Cytochrome P450-Specific Inhibition in Human Hepatic Microsomes

Zhang¹,

D'Esposito²,

Edwards³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The atypical antipsychotic drug clozapine (CLZ) is effective in a substantial number of patients who exhibit treatment-resistance to conventional agents. CYP1A2 is generally considered to be the major enzyme involved in the biotransformation of CLZ to its N-demethylated (norCLZ) and N-oxygenated (CLZ N-oxide) metabolites in liver, but several studies have also implicated CYP3A4. The present study assessed the interplay between these cytochrome P450s (P450s) in CLZ biotransformation in a panel of hepatic microsomal fractions from 14 individuals. The relative activity of P450s 1A2 and 3A4 in microsomes was found to be a major determinant of the relative susceptibility of norCLZ formation to inhibition by the P450-selective inhibitors fluvoxamine and ketoconazole. In contrast, the activity of CYP3A4 alone was correlated with the susceptibility of CLZ N-oxide formation to inhibition by these agents. These findings suggest that both P450s may be dominant CLZ oxidases in patients and that the relative activities of these enzymes may determine clearance pathways. In vivo assessment of CYP1A2 and CYP3A4 activities, perhaps by phenotyping approaches, could assist the optimization of CLZ dosage and minimize pharmacokinetic interactions with coadministered drugs.The atypical antipsychotic agent clozapine (CLZ) is effective in many patients who are resistant to treatment with conventional antipsychotic drugs, such as the phenothiazines and butyrophenones. However, its wider use is limited by interindividual variation in efficacy and toxicity. In vitro evidence suggests that the biotransformation of CLZ to its major metabolites N-desmethyl-CLZ (norCLZ) and CLZ N-oxide is catalyzed by hepatic cytochromes P450 (P450s) and flavin-containing monooxygenases (FMOs) (Pirmohamed et al., 1995). NorCLZ formation has been attributed to CYP1A2 and CYP3A4 (Pirmohamed et al., 1995;Linnet and Olesen, 1997) and CYP1A2 and CYP3A4, as well as the FMOs, catalyze CLZ N-oxygenation in vitro (Pirmohamed et al., 1995;Tugnait et al., 1997).There is wide interindividual variation in serum concentrations of CLZ and its active metabolite norCLZ, and the potential for pharmacokinetic drug-drug interactions in psychotic patients is high because of the likelihood of concurrent drug treatment. There have been numerous clinical reports that coadministration of alternate substrates and inhibitors of CYP1A2, such as the selective serotonin reuptake inhibitor fluvoxamine, fluoroquinolone antibacterials, and caffeine, inhibit CLZ clearance and mediate toxic interactions (Hiemke et al., 1994;Jerling et al., 1994). However, it has also been reported that drugs such as fluoxetine, paroxetine, and erythromycin, which inhibit CYP3A4 rather than CYP1A2, may also precipitate toxicity (Centorrino et al., 1996;Wetzel et al., 1998). The factors that determine individual susceptibility to CYP1A2 and CYP3A4 inhibition that leads to clinical toxicity are presently unclear.In a proportion of patients who receive CLZ therapeutic failure may occur because of rapid el...

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Section: Discussionmentioning

confidence: 99%

“…Efficacy in some patients may be established by coadministration of the CYP1A2 inhibitor fluvoxamine, which decreases CLZ elimination and restores therapeutic concentrations of the drug in serum (Ozdemir et al, 2001;Kontaxakis et al, 2005). Fluvoxamine is unlikely to be effective in patients who eliminate CLZ rapidly via CYP3A4.…”

mentioning

confidence: 99%

Interindividual Variation in Relative CYP1A2/3A4 Phenotype Influences Susceptibility of Clozapine Oxidation to Cytochrome P450-Specific Inhibition in Human Hepatic Microsomes

Zhang¹,

D'Esposito²,

Edwards³

et al. 2008

Drug Metab Dispos

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“…Another predictable interaction is that between fluvoxamine, a potent inhibitor of CYP1A2 [125,126], and clozapine. A 5 to 10-fold increase in the Cp of clozapine has been observed during the coadministration of clozapine and fluvoxamine [127][128][129][130][131].…”

Section: Interactions Due To Cyp1a2 Inhibitionmentioning

confidence: 99%

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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“…In vivo studies in patients have established that CYP1A2 has a major role in CLZ elimination. Exposure to CYP1A2 inducers, such as cigarette smoke chemicals, has been shown to increase CLZ clearance and to compromise therapy with the drug . Inhibitory DDIs with CYP1A2 substrates and inhibitors like fluvoxamine, caffeine and fluoroquinolone antibacterials also appear to be quite predictable .…”

Section: Discussionmentioning

confidence: 99%

“…A number of clinical studies have also shown that administration of drugs that inhibit CYP1A2, such as the selective serotinin reuptake inhibitor fluvoxamine, caffeine, the fluoroquinolone antibacterials and the antipsychotic agent perazine, inhibit CLZ clearance and can precipitate CLZ toxicity [2,[23][24][25][26]. In some psychiatric patients who smoke, fluvoxamine coadministration has been found to normalize CLZ clearance and restore therapeutic concentrations in serum [27,28]. There have been similar reports of DDIs with CYP3A4 inhibitors like erythromycin, fluoxetine and imidazole antifungal agents, which also precipitate toxicity by inhibiting CLZ elimination [29][30][31][32].…”

mentioning

confidence: 99%

Variation in the Response of Clozapine Biotransformation Pathways in Human Hepatic Microsomes to CYP1A2‐ and CYP3A4‐selective Inhibitors

Murray

Zhang

Edwards

2017

Basic Clin Pharma Tox

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The atypical antipsychotic agent clozapine (CLZ) is effective in many patients who are resistant to conventional antipsychotic drugs. Cytochromes P450 (CYPs) 1A2 and 3A4 oxidize CLZ to norCLZ and CLZ N-oxide in human liver. Concurrent treatment with inducers and inhibitors of CYP1A2 modulates CLZ elimination that disrupts therapy. Drug-drug interactions involving CYP3A4 are also significant but less predictable. To further characterize the factors underlying these interactions, we used samples from a cohort of human livers to assess variation in CLZ oxidation pathways in relation to intrinsic CYP3A4 and CYP1A2 activities and the effects of the corresponding selective inhibitors ketoconazole (0.2 and 2 μM) and fluvoxamine (1 and 10 μM). The CYP3A4-selective inhibitor ketoconazole (2 μM) impaired CLZ N-oxide formation in all 14 of the livers used in inhibition studies (≥50% inhibition) while the CYP1A2-selective inhibitor fluvoxamine (10 μM) decreased norCLZ formation in nine. Ketoconazole effectively inhibited CLZ metabolism in five of seven livers that catalysed CYP3A4-dependent testosterone 6β-hydroxylation at or above the median rate and in four other livers with lower intrinsic CYP3A4 activity. Similarly, fluvoxamine (10 μM) readily inhibited CLZ oxidation in seven livers with high CYP1A2-mediated 7-ethoxyresorufin O-deethylation activity (at or above the median) and three livers with lower intrinsic CYP1A2 activity. In three livers, CLZ biotransformation was impaired by both ketoconazole and fluvoxamine, consistent with a major role for both CYPs. These findings suggest that the intrinsic activities of CYPs 1A2 and 3A4 are unrelated to the response to CYP-selective inhibitors and that assessment of the activities in vivo may not assist the prediction of drug-drug interactions.

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Case Studies of Adjunctive Agents in Clozapine-Resistant Schizophrenic Patients

Cited by 17 publications

References 28 publications

Interindividual Variation in Relative CYP1A2/3A4 Phenotype Influences Susceptibility of Clozapine Oxidation to Cytochrome P450-Specific Inhibition in Human Hepatic Microsomes

Interindividual Variation in Relative CYP1A2/3A4 Phenotype Influences Susceptibility of Clozapine Oxidation to Cytochrome P450-Specific Inhibition in Human Hepatic Microsomes

CYP-Mediated Clozapine Interactions: How Predictable Are They?

Variation in the Response of Clozapine Biotransformation Pathways in Human Hepatic Microsomes to CYP1A2‐ and CYP3A4‐selective Inhibitors

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