Hepatotoxicity Associated With the New Antidepressants

García-Pando, Alfonso Carvajal; Pozo, Javier García del; Sánchez, A. Portera; Martín, Alfonso Velasco; Castro, Ana Maria Rueda de; Lucena, M. Isabel

doi:10.4088/jcp.v63n0208

Cited by 93 publications

(31 citation statements)

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“…Although the exact cause of hepatotoxicity by nefazodone is currently unknown, a probable causal link between nefazodone use and hepatic injury has been established based on the temporal relationship between nefazodone administration and the onset of hepatotoxicity in most cases. Furthermore, liver biopsy specimens from a patient who succumbed to the hepatic injury revealed marked centrozonal necrosis, which is consistent with a toxic etiology (García-Pando et al, 2002).…”

supporting

confidence: 57%

“…However, despite its therapeutic benefits, there are several reported cases of idiosyncratic adverse reactions including hepatobiliary dysfunction and cholestasis that are associated with the use of this drug (Aranda-Michel et al, 1999;Lucena et al, 1999;García-Pando et al, 2002;Stewart, 2002;Andrade and Lucena, 2003;Choi, 2003). The U.S. Food and Drug Administration has received reports of at least 55 cases of liver failure, including 20 deaths, and another 39 cases of less severe liver injury since nefazodone sales commenced in 1994.…”

mentioning

confidence: 99%

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Bioactivation of the Nontricyclic Antidepressant Nefazodone to a Reactive Quinone-Imine Species in Human Liver Microsomes and Recombinant Cytochrome P450 3a4

Kalgutkar¹,

Vaz²,

Lame³

et al. 2004

Drug Metab Dispos

150

116

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ABSTRACT:The therapeutic benefits of the antidepressant nefazodone have been hampered by several cases of acute hepatotoxicity/liver failure. Although the mechanism of hepatotoxicity remains unknown, it is possible that reactive metabolites of nefazodone play a causative role. Studies were initiated to determine whether nefazodone undergoes bioactivation in human liver microsomes to electrophilic intermediates. Following incubation of nefazodone with microsomes or recombinant P4503A4 in the presence of sulfydryl nucleophiles, conjugates derived from the addition of thiol to a monohydroxylated nefazodone metabolite were observed. Product ion spectra suggested that hydroxylation and sulfydryl conjugation occurred on the 3-chlorophenylpiperazine-ring, consistent with a bioactivation pathway involving initial formation of p-hydroxynefazodone, followed by its two-electron oxidation to the reactive quinone-imine intermediate. The formation of novel N-dearylated nefazodone metabolites was also discernible in these incubations, and 2-chloro-1,4-benzoquinone, a by-product of N-dearylation, was trapped with glutathione to afford the corresponding hydroquinone-sulfydryl adduct. Nefazodone also displayed NADPH-, time-, and concentration-dependent inactivation of P4503A4 activity, suggesting that reactive metabolites derived from nefazodone bioactivation are capable of covalently modifying P4503A4. A causative role for 2-chloro-1,4-benzoquinone and/or the quinone-imine intermediate(s) in nefazodone hepatotoxicity is speculated. Although the antianxiety agent buspirone, which contains a pyrimidine ring in place of the 3-chlorophenyl-ring, also generated phydroxybuspirone in liver microsomes, no sulfydryl conjugates of this metabolite were observed. This finding is consistent with the proposal that two-electron oxidation of p-hydroxybuspirone to the corresponding quinone-imine is less favorable due to differences in the protonation state at physiological pH and due to weaker resonance stabilization of the oxidation products as predicted from ab initio measurements.

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supporting

confidence: 57%

mentioning

confidence: 99%

Bioactivation of the Nontricyclic Antidepressant Nefazodone to a Reactive Quinone-Imine Species in Human Liver Microsomes and Recombinant Cytochrome P450 3a4

Kalgutkar¹,

Vaz²,

Lame³

et al. 2004

Drug Metab Dispos

150

116

View full text Add to dashboard Cite

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“…Although it is generally considered safe, acute liver failure due to sertraline use has been documented [91][92][93][94][95][96][97][98][99]. Sertraline was demonstrated to be toxic in primary rat hepatocytes and human HepG2 cells; mitochondrial dysfunction and apoptosis are the underlying mechanisms [100,101].…”

Section: Anti-depression Drugsmentioning

confidence: 99%

Endoplasmic Reticulum Stress in Drug- and Environmental Toxicant-Induced Liver Toxicity

Chen

Melchior

Guo

2014

Journal of Environmental Science and Health, Part C

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Liver injury resulting from exposure to drugs and environmental chemicals is a major health problem. Endoplasmic reticulum stress (ER stress) is considered to be an important factor in a wide range of diseases, such as cancer, neurological and cardiovascular disease, diabetes, and inflammatory diseases. The role of ER stress in drug-induced and environmental toxicant-induced liver toxicity has been underestimated in the past; emerging evidence indicates that ER stress makes a substantial contribution to the pathogenesis of drug-induced liver toxicity. In this review, we summarize current knowledge on drugs and environmental toxicants that trigger ER stress in liver and on the underlying molecular mechanisms. We also discuss experimental approaches for ER stress studies.

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“…SSRIs and selective noradrenergic reuptake inhibitors (SNRIs) have been associated with hepatoxicity in isolated reports in non-CLD patients which reversed on discontinuation of the drug, including venlafaxine, 78 citalopram, 87 and fluoxetine, paroxetine and sertraline. 88 In a series of seven cases of duloxetine-induced liver injury, three had pre-existing chronic liver disease and one had acute decompensation with jaundice and ascites. 89 Both duloxetine and sertraline have also been associated with fatal hepatotoxicity.…”

mentioning

confidence: 99%

Review article: depression and the use of antidepressants in patients with chronic liver disease or liver transplantation

Mullish

Kabir

Thursz

et al. 2014

Aliment Pharmacol Ther

116

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SummaryBackgroundThe scale of depression in patients with chronic liver disease (CLD) and those who have received orthotopic liver transplantation (OLT) is poorly characterised. Clinicians are uncertain of how best to manage depression within these patients.AimsTo review the literature evaluating both the prevalence and impact of depression in patients with CLD and post‐OLT, and to assess the safety and efficacy of antidepressant use within this context.MethodsA PubMed search using the phrases ‘chronic liver disease’, ‘cirrhosis’, ‘liver transplantation’, ‘depression’, ‘antidepressant’ and the names of specific causes of liver disease and individual antidepressants.ResultsOver 30% of cirrhotic patients have depressive features, and they experience worse clinical outcomes than nondepressed cirrhotic patients. CLD patients with chronic hepatitis C are particularly prone to depression, partly related to the use of interferon therapy. OLT patients with depression have higher mortality rates than nondepressed patients; appropriate antidepressant use reverses this effect. Selective serotonin reuptake inhibitors (SSRIs) and selective noradrenaline reuptake inhibitors (SNRIs) are effective and generally safe in both CLD and OLT patients.ConclusionsDepression is much more prevalent in CLD or OLT patients than is generally recognised, and it adversely affects clinical outcomes. The reasons for this relationship are complex and multifactorial. Antidepressants are effective in both CLD and post‐OLT, although lower doses or a reduced dosing frequency may be required to minimise side effects, e.g. exacerbation of hepatic encephalopathy. Further research is needed to establish optimal management of depression in these patients, including the potential role of nonpharmacological treatments.

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Hepatotoxicity Associated With the New Antidepressants

Cited by 93 publications

References 0 publications

Bioactivation of the Nontricyclic Antidepressant Nefazodone to a Reactive Quinone-Imine Species in Human Liver Microsomes and Recombinant Cytochrome P450 3a4

Bioactivation of the Nontricyclic Antidepressant Nefazodone to a Reactive Quinone-Imine Species in Human Liver Microsomes and Recombinant Cytochrome P450 3a4

Endoplasmic Reticulum Stress in Drug- and Environmental Toxicant-Induced Liver Toxicity

Review article: depression and the use of antidepressants in patients with chronic liver disease or liver transplantation

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