Fatal acute fulminant liver failure due to clozapine: A case report and review of clozapine-induced hepatotoxicity

Macfarlane, B; Davies, Susan; Mannan, Khalid; Sarsam, R; Pariente, D.; Dooley, James

doi:10.1016/s0016-5085(97)70054-4

Cited by 77 publications

(48 citation statements)

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“…It was reported that at least 1000 kinds of drugs can cause DILI. Accumulating evidences have showed that about 50% of the patients treated with CLZ were associated with increases in hepatic enzymes including AST and ALT (40,41,42). DILI by CLZ commonly occurred within the first weeks of treatment (43).…”

Section: Discussionmentioning

confidence: 99%

The Aggravation of Clozapine-Induced Hepatotoxicity by Glycyrrhetinic Acid in Rats

Jia

Zhong

et al. 2014

J Pharmacol Sci

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Abstract. Clozapine (CLZ) was reported to be associated with hepatotoxicity. Glycyrrhetinic acid (GA) has a liver protective effect. Our preliminary experiments showed that GA aggravated rather than attenuated CLZinduced hepatotoxicity in primary cultured rat hepatocytes. The study aimed to describe the enhancing effect of GA on CLZinduced hepatotoxicity in vivo and in vitro. Data from primary cultured rat hepatocytes showed the decreased formation of metabolites demethylclozapine (norCLZ) and clozapine Noxide (CLZ Noxide) .The results in vivo showed that 7day CLZ treatment led to marked accumulation of triglyceride (TG) and increase in g glutamyl transpeptidase (gGT) activity, liver weight, and serum AST in rats. Coadministration of GA enhanced the increases in hepatic TG, gGT, liver weight, and serum total cholesterol induced by CLZ. GA decreased plasma concentrations of norCLZ and CLZ Noxide. Compared with control rats, hepatic microsomes of GA rats exhibited the decreased formations of norCLZ and CLZ Noxide, accompanied by decreases in activities of CYP2C11 and CYP2C19 and increased activity of CYP1A2. QTPCR analysis demonstrated that GA enhanced expression of CYP1A2, but suppressed expression of CYP2C11 and CYP2C13. All these results support the conclusion that GA aggravated CLZinduced hepatotoxicity, which was partly via inhibiting CYP2C11 and CYP2C13 or inducing CYP1A2.

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Section: Discussionmentioning

confidence: 99%

The Aggravation of Clozapine-Induced Hepatotoxicity by Glycyrrhetinic Acid in Rats

Jia

Zhong

et al. 2014

J Pharmacol Sci

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“…These results are in agreement with several previous reports. (Worrall et al, 1995;Macfarlane et al, 1997;Luo et al, 2007;Chang et al, 2009). Marinkovic et al (1994) and Worrall et al (1995) reported dose-dependent elevation of hepatic enzymes with clozapine therapy.…”

Section: Kilianmentioning

confidence: 99%

“…However, they suggested that continuing clozapine treatment might be possible in some patients. Macfarlane et al (1997) described a case of fatal acute fulminant liver failure caused by clozapine. On the other hand, Kilian et al (1999) reported mild inflammation in the portal tracts of the liver associated with eosinophilic infiltrates in a case that died 18 days after starting clozapine treatment.…”

Section: Kilianmentioning

confidence: 99%

Cardiotoxicity and Hepatotoxicity Induced by Clozapine in Adult Male Albino Rats and Possible Protection by Selenium: A Histological Study

Kamel

2011

The Egyptian Journal of Anatomy

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Background: Clozapine is an efficacious antipsychotic drug particularly in schizophrenic patients refractory to other agents. Treatment with clozapine was reported to be associated with sudden death, myocarditis and hepatotoxicity in some patients. Aim of the Work: This study was conducted to investigate the toxic effect of clozapine on cardiac muscle and liver of adult male albino rats and to assess the potential protective role of selenium. Materials and Methods:This study employed fifty adult male albino rats randomly divided into five equal groups. Group I: Control group, Group II received daily 1 ml of 0.1 M HCl, balanced in phosphate buffered saline intraperitoneally (i.p.), Group III received oral selenium (1.5 mg/kg), Group IV received Clozapine (25 mg/kg) i.p. daily and Group V received both clozapine and selenium. After 14 days, the liver and ventricular myocardium of each animal were dissected and processed for light and electron microscopic studies. Results: After clozapine administration, the ventricular myocardium showed fragmentation and separation of cardiac muscles with diffuse mixed inflammatory cellular infiltrate. The Z-lines were irregularly oriented with rupture of mitochondrial membranes and cristae. The liver exhibited extensive inflammatory cellular infiltration around the portal areas and vacuolated hepatocyte cytoplasm with rupture of membranes and cristae of some mitochondria. Concomitant administration of selenium with clozapine displayed an observable protection against these changes. Conclusion: Selenium may have a protective role against cardiotoxicity and hepatotoxicity induced by clozapine therapy.

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“…at ASPET Journals on May 7, 2018 dmd.aspetjournals.org ulocytosis, and hepatotoxicity and received a warning regarding its use (Alvir et al, 1993;Macfarlane et al, 1997). Clozapine forms reactive metabolites such as nitrenium ion by P450s, activated neutrophils, and bone marrow cells (Pirmohamed et al, 1995).…”

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confidence: 99%

Markers of Electrophilic Stress Caused by Chemically Reactive Metabolites in Human Hepatocytes

Takakusa¹,

Masumoto²,

Mitsuru³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The metabolic activation of a drug to an electrophilic reactive metabolite and its covalent binding to cellular macromolecules is considered to be involved in the occurrence of idiosyncratic drug toxicity (IDT). As a cellular defense system against oxidative and electrophilic stress, phase II enzymes are known to be induced through a Kelchlike ECH-associated protein 1/nuclear factor E2-related factor 2/antioxidant response element system. We presumed that it is important for the risk assessment of drug-induced hepatotoxicity and IDTs to observe the biological responses evoked by exposure to reactive metabolites, and then investigated the mRNA induction profiles of phase II enzymes in human hepatocytes after exposure to problematic drugs associated with IDTs, such as ticlopidine, diclofenac, clozapine, and tienilic acid, as well as safe drugs such as levofloxacin and caffeine. According to the results, the problematic drugs exhibited inductive effects on heme oxygenase 1 (HO-1), which contrasted with the safe drugs; therefore, the induction of HO-1 mRNA seems to be correlated with the occurrence of drug toxicity, including IDT caused by electrophilic reactive metabolites. Moreover, glutathionedepletion and cytochrome P450 (P450)-inhibition experiments have shown that the observed HO-1 induction was triggered by the electrophilic reactive metabolites produced from the problematic drugs through P450-mediated metabolic bioactivation. Taken together with our present study, this suggests that HO-1 induction in human hepatocytes would be a good marker of the occurrence of metabolismbased drug-induced hepatotoxicity and IDT caused by the formation of electrophilic reactive metabolites.

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Fatal acute fulminant liver failure due to clozapine: A case report and review of clozapine-induced hepatotoxicity

Cited by 77 publications

References 0 publications

The Aggravation of Clozapine-Induced Hepatotoxicity by Glycyrrhetinic Acid in Rats

The Aggravation of Clozapine-Induced Hepatotoxicity by Glycyrrhetinic Acid in Rats

Cardiotoxicity and Hepatotoxicity Induced by Clozapine in Adult Male Albino Rats and Possible Protection by Selenium: A Histological Study

Markers of Electrophilic Stress Caused by Chemically Reactive Metabolites in Human Hepatocytes

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