Erythromycin-Induced Clozapine Toxic Reaction

Cohen, Louise Glassner; Chesley, Shelley; Eugenio, L. E.; Flood, James G.; Fisch, Judith E.; Goff, Donald C.

doi:10.1001/archinte.1996.00440060103013

Cited by 53 publications

(8 citation statements)

References 10 publications

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“…Although it appears that CYP3A4 is without common functional polymorphisms (Hiratsuka, 2012), it has been shown that nonsynonymous alleles for CYP3A4 encode enzymes with altered catalytic properties (Dai et al, 2001;Eiselt et al, 2001;Zhang et al, 2008). Inducers that increase the activity of CYP3A4 (Cohen et al, 1996;Jerling et al, 1994) could be more important than genetic polymorphism of this enzyme for the individual variability in CLZ bioactivation. Although CYP2D6 showed relatively high specific activity in all three oxidative pathways of CLZ-metabolism (Table 1), the CYP2D6-specific inhibitor quinidine showed no or only minor inhibition of these pathways in incubations of CLZ with the 100 individual HLM fractions (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Human Cytochrome P450s Involved in the Bioactivation of Clozapine

et al. 2013

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Clozapine is known to cause hepatotoxicity in a small percentage of patients. Oxidative bioactivation to reactive intermediates by hepatic cytochrome P450s (P450s) has be proposed as a possible mechanism. However, in contrast to their role in formation of N-desmethylclozapine and clozapine N-oxide, the involvement of individual P450s in the bioactivation to reactive intermediates is much less well characterized. The results of the present study show that 7 of 14 recombinant human P450s were able to bioactivate clozapine to a glutathione-reactive nitrenium ion. CYP3A4 and CYP2D6 showed the highest specific activity. Enzyme kinetical characterization of these P450s showed comparable intrinsic clearance of bioactivation, implicating that CYP3A4 would be more important because of its higher hepatic expression, compared with CYP2D6. Inhibition experiments using pooled human liver microsomes confirmed the major role of CYP3A4 in hepatic bioactivation of clozapine. By studying bioactivation of clozapine in human liver microsomes from 100 different individuals, an 8-fold variability in bioactivation activity was observed. In two individuals bioactivation activity exceeded N-demethylation and Noxidation activity. Quinidine did not show significant inhibition of bioactivation in any of these liver fractions, suggesting that CYP2D6 polymorphism is not an important factor in determining susceptibility to hepatotoxicity of clozapine. Therefore, interindividual differences and drug-drug interactions at the level of CYP3A4 might be factors determining exposure of hepatic tissue to reactive clozapine metabolites.

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Section: Discussionmentioning

confidence: 99%

Characterization of Human Cytochrome P450s Involved in the Bioactivation of Clozapine

et al. 2013

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“…Despite the established role of CYP1A2, there have also been a number of clinical reports that have implicated CYP3A4 in CLZ elimination. Thus, erythromycin increased CLZ plasma levels and precipitated seizures or other adverse drug interactions in some patients (Funderburg et al, 1994;Cohen et al, 1996;Edge et al, 1997). Likewise, coadministration of the selective serotonin reuptake inhibitor drugs fluoxetine and paroxetine increased serum concentrations of CLZ up to 60% over control in some patients, possibly due to inhibition of CYP3A4 (Centorrino et al, 1994(Centorrino et al, , 1996Wetzel et al, 1998;Diaz et al, 2008).…”

Section: Discussionmentioning

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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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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“…Controversial findings have been reported concerning the interaction between erythromycin, a macrolide antibiotic with a strong inhibitory effect on CYP3A4, and clozapine. Case reports have indicated that concomitant treatment with erythromycin resulted in an elevation of plasma clozapine levels, along with toxic effects [181,182]. Conversely, in a study in healthy subjects, no modifications in the disposition of clozapine during coadministration with erythromycin, suggesting a limited involvement of CYP3A4 in the metabolism of clozapine in humans [183].…”

Section: Clozapinementioning

confidence: 99%

Metabolic drug interactions with new psychotropic agents

Spina

Scordo

D'Arrigo

2003

Fundamemntal Clinical Pharma

118

104

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New psychotropic drugs introduced in clinical practice in recent years include new antidepressants, such as selective serotonin reuptake inhibitors (SSRI) and 'third generation' antidepressants, and atypical antipsychotics, i.e. clozapine, risperidone, olanzapine, quetiapine, ziprasidone and amisulpride. These agents are extensively metabolized in the liver by cytochrome P450 (CYP) enzymes and are therefore susceptible to metabolically based drug interactions with other psychotropic medications or with compounds used for the treatment of concomitant somatic illnesses. New antidepressants differ in their potential for metabolic drug interactions. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, fluvoxamine markedly inhibits CYP1A2 and CYP2C19, while nefazodone is a potent inhibitor of CYP3A4. These antidepressants may be involved in clinically significant interactions when coadministered with substrates of these isoforms, especially those with a narrow therapeutic index. Other new antidepressants including sertraline, citalopram, venlafaxine, mirtazapine and reboxetine are weak in vitro inhibitors of the different CYP isoforms and appear to have less propensity for important metabolic interactions. The new atypical antipsychotics do not affect significantly the activity of CYP isoenzymes and are not expected to impair the elimination of other medications. Conversely, coadministration of inhibitors or inducers of the CYP isoenzymes involved in metabolism of the various antipsychotic compounds may alter their plasma concentrations, possibly leading to clinically significant effects. The potential for metabolically based drug interactions of any new psychotropic agent may be anticipated on the basis of knowledge about the CYP enzymes responsible for its metabolism and about its effect on the activity of these enzymes. This information is essential for rational prescribing and may guide selection of an appropriate compound which is less likely to interact with already taken medication(s).

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Erythromycin-Induced Clozapine Toxic Reaction

Cited by 53 publications

References 10 publications

Characterization of Human Cytochrome P450s Involved in the Bioactivation of Clozapine

Characterization of Human Cytochrome P450s Involved in the Bioactivation of Clozapine

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

Metabolic drug interactions with new psychotropic agents

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