Acute hepatocellular injury associated with zafirlukast

Molés, J R; Primo, J; Fernández, J. Martínez; Hinojosa, Joaquín

doi:10.1016/s0168-8278(01)00124-6

Cited by 18 publications

(5 citation statements)

References 8 publications

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“…59,60 Onset of symptoms was delayed until 5 to 13 months after starting zafirlukast treatment but can occur as early as 8 weeks after starting this agent. 61 Inadvertent rechallenge reproduced the liver injury in one case. 59 Explant liver or needle liver biopsies have shown submassive or massive hepatic necrosis.…”

Section: Newer Anti-inflammatory Drugsmentioning

confidence: 94%

“…Clinically significant hepatic injury has been reported in six persons (five women). [59][60][61][62] Two developed acute liver failure and have needed liver transplantation. 59,60 Onset of symptoms was delayed until 5 to 13 months after starting zafirlukast treatment but can occur as early as 8 weeks after starting this agent.…”

Section: Newer Anti-inflammatory Drugsmentioning

confidence: 99%

“…However, the absence of hypersensitivity characteristics in other reports suggests metabolic idiosyncrasy. 60,61…”

Section: Newer Anti-inflammatory Drugsmentioning

confidence: 99%

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Hepatotoxicity of Commonly Used Drugs: Nonsteroidal Anti-Inflammatory Drugs, Antihypertensives, Antidiabetic Agents, Anticonvulsants, Lipid-Lowering Agents, Psychotropic Drugs

Chitturi¹,

George²

2002

Semin Liver Dis

194

106

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Hepatotoxic adverse drug reactions have contributed to the decline of many promising therapies, even among mainstream medication classes (bromfenac and troglitazone are recent examples). The spectrum of nonsteroidal anti-inflammatory drug-related liver toxicity continues to expand, with reports in children, interactive toxicity in persons with hepatitis C, and recognition of the toxicity of both the preferential and selective cyclooxygenase-2 inhibitors. Of the antihypertensive agents, methyldopa is now rarely prescribed and adverse effects are reported infrequently, whereas cases of liver injury associated with the angiotensin receptor and converting enzyme inhibitors are increasingly reported. Of the antidiabetic agents, acarbose, gliclazide, metformin, and human insulin have been implicated in causing liver injury. To date, the newer thiazolidinediones do not appear to share the hepatotoxic potential of troglitazone, although a few reports of acute hepatitis have accrued. Although liver injury has been associated with the "statins," the frequency of such toxicity is lower than that of the background population and the value of biochemical monitoring remains unproved. Newer concepts in anticonvulsant hepatotoxicity have been the recognition of the reactive metabolite syndrome, delineation of the risk factors for valproic acid toxicity, the potential role of carnitine in preventing valproic acid hepatotoxicity, and the toxicity of second-line antiepileptic drugs. Liver injury associated with newer psychotropic agents, particularly the selective serotonin reuptake inhibitors, is also discussed. The focus of the review is the hepatotoxicity of commonly used drugs with particular reference to recent and novel reports of toxicity. Well-known causes of liver injury such as chlorpromazine, phenytoin, and methyldopa are not discussed.

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Section: Newer Anti-inflammatory Drugsmentioning

confidence: 94%

Section: Newer Anti-inflammatory Drugsmentioning

confidence: 99%

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Hepatotoxicity of Commonly Used Drugs: Nonsteroidal Anti-Inflammatory Drugs, Antihypertensives, Antidiabetic Agents, Anticonvulsants, Lipid-Lowering Agents, Psychotropic Drugs

Chitturi¹,

George²

2002

Semin Liver Dis

194

106

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“…Zafirlukast (Accolate) is a leukotriene receptor antagonist which is used clinically to treat mild to moderate asthma. Several isolated cases of idiosyncratic hepatotoxicity have been associated with the use of zafirlukast (1)(2)(3). Clinical reports describing the hepatotoxicity characterize it as an idiosyncratic drug reaction based on several factors including the following: other pathophysiological causes of hepatic disease were eliminated; liver biopsy results were consistent with toxic injury; systemic hypersensitivity was observed in at least one case; and rechallenge with zafirlukast produced recurrent hepatitis (1).…”

Section: Introductionmentioning

confidence: 99%

Zafirlukast Metabolism by Cytochrome P450 3A4 Produces an Electrophilic α,β-Unsaturated Iminium Species That Results in the Selective Mechanism-Based Inactivation of the Enzyme

Kassahun

Skordos

McIntosh

et al. 2005

Chem. Res. Toxicol.

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Zafirlukast is a leukotriene antagonist indicated for the treatment of mild to moderate asthma, but the drug has been associated with occasional idiosyncratic hepatotoxicity. Structurally, zafirlukast is similar to 3-methylindole because it contains an N-methylindole moiety that has a 3-alkyl substituent on the indole ring. The results presented here describe the metabolic activation of zafirlukast via a similar mechanism to that described for 3-methylindole. NADP(H)-dependent biotransformation of zafirlukast by hepatic microsomes from rats and humans afforded a reactive metabolite, which was detected as its GSH adduct. Mass spectrometry and NMR data indicated that the GSH adduct was formed by the addition of GSH to the methylene carbon between the indole- and methoxy-substituted phenyl rings of zafirlukast. The formation of this reactive metabolite in human liver microsomes was shown to be exclusively catalyzed by CYP3A enzymes. Evidence for in vivo metabolic activation of zafirlukast was obtained when the same GSH adduct was detected in bile of rats given an iv or oral dose of the drug. On the basis of results with model peroxidases and of the structures of product alcohols from incubations containing H2(18)O, it appeared that zafirlukast underwent dehydrogenation by two sequential one-electron oxidations. In addition, zafirlukast proved to be a mechanism-based inhibitor of CYP3A4 activity in human liver microsomes and in microsomes containing cDNA-expressed CYP3A4. The enzyme inhibitory property of zafirlukast was selective for this enzyme among all of the P450 enzymes that were tested in human liver microsomes. The inactivation was characterized by a K(I) of 13.4 microM and k(inact) of 0.026 min(-1). In summary, zafirlukast dehydrogenation to an electrophilic alpha,beta-unsaturated iminium intermediate may be associated with idiosyncratic hepatotoxicity and/or cause drug-drug interactions through inactivation of CYP3A4.

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“…1 Hepatotoxicity has been associated with not only zafir-lukast, but recent reports have also described elevated liver enzyme levels, hepatitis, and fulminant he-patic failure induced by montelu-kast. [2][3][4][5][6][7][8] However, all the described cases are adult patients and there have been no similar reports with montelukast in children. We pres-ent a patient who we believe is the first pediatric case of acute hepati-tis while receiving montelukast.…”

mentioning

confidence: 98%

Probable montelukast-induced hepatotoxicity in a pediatric patient : Case report

İncecik¹,

Önlen²,

Sangün³

et al. 2007

Ann Saudi Med

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Acute hepatocellular injury associated with zafirlukast

Cited by 18 publications

References 8 publications

Hepatotoxicity of Commonly Used Drugs: Nonsteroidal Anti-Inflammatory Drugs, Antihypertensives, Antidiabetic Agents, Anticonvulsants, Lipid-Lowering Agents, Psychotropic Drugs

Hepatotoxicity of Commonly Used Drugs: Nonsteroidal Anti-Inflammatory Drugs, Antihypertensives, Antidiabetic Agents, Anticonvulsants, Lipid-Lowering Agents, Psychotropic Drugs

Zafirlukast Metabolism by Cytochrome P450 3A4 Produces an Electrophilic α,β-Unsaturated Iminium Species That Results in the Selective Mechanism-Based Inactivation of the Enzyme

Probable montelukast-induced hepatotoxicity in a pediatric patient : Case report

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