Hepatic injury caused by benzbromarone

Klauw, Melanie M. van der; Houtman, P. M.; Stricker, Bruno H. Ch.; Spoelstra, P.

doi:10.1016/s0168-8278(94)80011-1

Cited by 68 publications

(30 citation statements)

References 9 publications

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“…Patients receiving combination therapy of benzbromarone with S-warfarin experienced increased bleeding events [1357]. Such drug interactions may provide partial explanation for a few cases of hepatotoxicity associated with poor clearance of benzbromarone and its analogs [1546], such as benziodarone and benzarone [1547]. Amiodarone, an analog of benzbromarone, has been found to decrease the clearance of warfarin in vivo [1345].…”

Section: Drug-drug Interactions Owing To Cyp2c9 Inhibitionmentioning

confidence: 99%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

147

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Cytochrome P450 2C9 (CYP2C9) is one of the most abundant CYP enzymes in the human liver. CYP2C9 metabolizes more than 100 therapeutic drugs, including tolbutamide, glyburide, diclofenac, celecoxib, torasemide, phenytoin losartan, and S-warfarin). Some natural and herbal compounds are also metabolized by CYP2C9, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Many CYP2C9 substrates are weak acids, but CYP2C9 also has the capacity to metabolise neutral, highly lipophilic compounds. A number of ligand-based and homology models of CYP2C9 have been reported and this has provided insights into the binding of ligands to the active site of CYP2C9. Data from the site-directed mutagenesis studies have revealed that a number of residues (e.g. Arg97, Phe110, Val113, Phe114, Arg144, Ser286, Asn289, Asp293 and Phe476) play an important role in ligand binding and determination of substrate specificity. The resolved crystal structures of CYP2C9 have confirmed the importance of these residues in substrate recognition and ligand orientation. CYP2C9 is activated by dapsone and its analogues and R-lansoprazole in a stereo-specific and substrate-dependent manner, probably through binding to the active site and inducing positive cooperativity. CYP2C9 is subject to induction by rifampin, phenobarbital, and dexamethasone, indicating the involvement of pregnane X receptor, constitutive androstane receptor and glucocorticoid receptor in the regulation of CYP2C9. A number of compounds have been found to inhibit CYP2C9 and this may provide an explanation for some clinically important drug interactions. Tienilic acid, suprofen and silybin are mechanism-based inhibitors of CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates, inducer or inhibitors of CYP2C9 in drug development and drug discovery scientists should develop drugs with minimal interactions with this enzyme. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships.

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Section: Drug-drug Interactions Owing To Cyp2c9 Inhibitionmentioning

confidence: 99%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

147

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“…The reason for the withdrawal was the risk of fulminant hepatitis according to the information given by the manufacturer. Since the introduction of benzbromarone in the early 1970s, three cases of severe hepatitis have been published [2][3][4]. On the other hand, benzbromarone seems well tolerated in general use [5] in contrast to allopurinol, which causes frequently (2-5%) allergic skin reactions.…”

Section: Introductionmentioning

confidence: 99%

Biochemical effectiveness of allopurinol and allopurinol-probenecid in previously benzbromarone-treated gout patients

et al. 2007

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“…1, the structures of benzbromarone as well as benzarone are closely related to that of amiodarone. This structural relationship coupled with the fact that these two drugs can also cause hepatic injury, 9 in some patients with fatal outcome, 8,10 led us to hypothesize that their mechanism of toxicity may be similar to that of amiodarone. In support of our hypothesis, it has been shown that benzbromarone can inhibit several enzyme complexes of the electron transport chain in isolated mouse liver mitochondria.…”

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confidence: 99%

Mechanisms of benzarone and benzbromarone-induced hepatic toxicity

et al. 2005

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Treatment with benzarone or benzbromarone can be associated with hepatic injury. Both drugs share structural similarities with amiodarone, a well-known mitochondrial toxin. Therefore, we investigated the hepatotoxicity of benzarone and benzbromarone as well as the analogues benzofuran and 2-butylbenzofuran. In isolated rat hepatocytes, amiodarone, benzarone, and benzbromarone (20 mol/L) decreased mitochondrial membrane potential by 23%, 54% or 81%, respectively. Benzofuran and 2-butylbenzofuran had no effect up to 100 mol/L. In isolated rat liver mitochondria, amiodarone, benzarone, and benzbromarone, but not benzofuran, decreased state 3 oxidation and respiratory control ratios for L-glutamate (50% decrease of respiratory control ratio at [mol/L]: amiodarone, 12.9; benzarone, 10.8; benzbromarone, <1). Amiodarone, benzarone, and benzbromarone, but not benzofuran, also uncoupled oxidative phosphorylation. Mitochondrial ␤-oxidation was decreased by 71%, 87%, and 58% with 100 mol/L amiodarone or benzarone and 50 mol/L benzbromarone, respectively, but was unaffected by benzofuran, whereas ketogenesis was not affected. 2-Butylbenzofuran weakly inhibited state 3 oxidation and ␤-oxidation only at 100 mol/L. In the presence of 100 mol/L amiodarone, benzarone or benzbromarone, reactive oxygen species production was increased, mitochondrial leakage of cytochrome c was induced in HepG2 cells, and permeability transition was induced in isolated rat liver mitochondria. At the same concentrations, amiodarone, benzarone, and benzbromarone induced apoptosis and necrosis of isolated rat hepatocytes. In conclusion, hepatotoxicity associated with amiodarone, benzarone, and benzbromarone can at least in part be explained by their mitochondrial toxicity and the subsequent induction of apoptosis and necrosis. Side chains attached to the furan moiety are necessary for rendering benzofuran hepatotoxic.

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Hepatic injury caused by benzbromarone

Cited by 68 publications

References 9 publications

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Biochemical effectiveness of allopurinol and allopurinol-probenecid in previously benzbromarone-treated gout patients

Mechanisms of benzarone and benzbromarone-induced hepatic toxicity

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