Elevated Levels of Clozapine in Serum After Addition of Fluvoxamine

Hiemke, Christoph; Weigmann, Harald; Härtter, Sebastian; Dahmen, Norbert; Wetzel, Hermann; Müller, Hj.

doi:10.1097/00004714-199408000-00011

Cited by 153 publications

(51 citation statements)

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“…Thus, drug interactions in which serum levels of CLZ are increased in patients by the CYP1A2 inhibitors and substrates fluvoxamine, ciprofloxacin, and caffeine have been reported widely (Hiemke et al, 1994;Jerling et al, 1994;Raaska and Neuvonen, 2000). Indeed, fluvoxamine decreased CLZ clearance severalfold (Hiemke et al, 1994;Wang et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

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%

Section: Introductionmentioning

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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“…While fluvoxamine appears to affect minimally and in a dosedependent manner the elimination of risperidone, it should be pointed out that this agent, already at the dose of 100 mg/day, may cause a significant elevation of plasma concentration of various antipsychotics, such as haloperidol (1.8-4.2-fold increase), clozapine (up to 5-10-fold) and olanzapine (up to 2-fold), due to its potent inhibitory effect on CYP1A2, CYP2C19 and, to a lesser extent, CYP3A4, the major CYP isoforms involved in the biotransformation of these compounds [32][33][34][35].…”

Section: Discussionmentioning

confidence: 99%

Effect of fluvoxamine on plasma risperidone concentrations in patients with schizophrenia

D'Arrigo

Migliardi

Santoro

et al. 2005

Pharmacological Research

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The effect of fluvoxamine on plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) was investigated in 11 schizophrenic patients with prevailingly negative or depressive symptoms. Additional fluvoxamine, at the dose of 100 mg/day, was administered for 4 weeks to patients stabilized on risperidone (3-6 mg/day). Mean plasma concentrations of risperidone, 9-OH-risperidone and the active moiety (sum of the concentrations of risperidone and 9-OH-risperidone) were not significantly modified following co-administration with fluvoxamine. After 4 weeks, fluvoxamine dosage was increased to 200 mg/day in five patients and then maintained until the end of week 8. At final evaluation, mean plasma levels of risperidone active moiety were not modified in the six patients who were still receiving the initial fluvoxamine dose, while concentrations increased slightly but significantly (by a mean 26% over pretreatment; P < 0.05) in the subgroup of five subjects treated with a final dose of 200 mg/day. Fluvoxamine co-administration with risperidone was well tolerated and no patient developed extrapyramidal side effects. These findings indicate that fluvoxamine at dosages up to 100 mg/day is not associated with clinically significant changes in plasma risperidone concentrations. However, higher doses of fluvoxamine may elevate plasma risperidone levels, presumably as a result of a dose-dependent inhibitory effect of fluvoxamine on CYP2D6-and/or CYP3A4-mediated 9-hydroxylation of risperidone.

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“…In agreement with this, we showed that phenacetin was a weak inhibitor of the formation of all three theophylline metabolites. Furthermore the neuroleptic drug, clozapine, a putative substrate for CYP1A2 [40][41][42][43], was also a weak inhibitor of the three major pathways.…”

Section: Discussionmentioning

confidence: 99%

Selective serotonin reuptake inhibitors and theophylline metabolism in human liver microsomes: potent inhibition by fluvoxamine.

Rasmussen¹,

Mäenpää²,

Pelkonen³

et al. 1995

Brit J Clinical Pharma

141

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1 Fluvoxamine and seven other selective serotonin reuptake inhibitors (SRRI) were tested for their ability to inhibit a number of human cytochrome P450 isoforms (CYPs). 2 None of the drugs showed potent inhibition of CYP2A6 (coumarin 7-hydroxylase) or CYP2E1 (chlorzoxazone 6-hydroxylase), while norfluoxetine was the only 5 Ethanol inhibited the formation of 1,3-dimethyluric acid with a Ki value of 300 JM, a value which is consistent with inhibition of CYP2E1. Ethanol and fluvoxamine both inhibited 8-hydroxylation by about 45% and, in combination, the compounds decreased the formation of 1,3-dimethyluric acid by 90%, indicating that CYP1A2 and CYP2E1 are equally important isoforms for the 8-hydroxylation of theophylline. 6 It is concluded that pharmacokinetic interaction between fluvoxamine and theophylline is due to potent inhibition of CYP1A2.

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Elevated Levels of Clozapine in Serum After Addition of Fluvoxamine

Cited by 153 publications

References 0 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

Effect of fluvoxamine on plasma risperidone concentrations in patients with schizophrenia

Selective serotonin reuptake inhibitors and theophylline metabolism in human liver microsomes: potent inhibition by fluvoxamine.

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