Idiosyncratic hepatotoxicity

Flutamide, an antiprostate cancer drug, is another example where inhibition of ETS, primarily at complex I, is associated with hepatotoxicity [56, 57]. Nefazodone, an antidepressant, also inhibits complex I activity and was discontinued in 2004 due to idiosyncratic hepatotoxicity [58]. 

Li, A.P. (2002) A review of the common properties of drugs with idiosyncratic hepatotoxicity and the multiple determinant hypothesis for the manifestation of idiosyncratic drug toxicity. Ctemico-Bioiogicoi Interactions, 142 (1-2), 7-23. 

Rumboldt Z, Bota B. Favorable effects of glibenclamide in a patient exhibiting idiosyncratic hepatotoxic reactions to both chlorpropamide and tolbutamide. Acta Diabetol Lat 1984 21(4) 387-91. 

Ethosuximide was introduced in 1960 as the third of three marketed succinimides in the USA. Ethosuximide has very little activity against maximal electroshock but considerable efficacy against pentylenetetrazol seizures and was introduced as a "pure petit mal" drug. Its continued popularity is based on its safety and efficacy, and its role as the first choice anti-absence drug remains undiminished—in part because of the idiosyncratic hepatotoxicity of the alternative drug, valproic acid. 

Sodium valproate is useful in the control of most seizure types and has the shortest half-life of the commonly used anticonvulsants (4—15 hours) a slowly absorbed form of the drug, divalproex sodium, is sometimes preferred. Valproate is relatively free from cognitive and behavioural side effects, but alopecia and weight gain frequently occur. The most severe side effect is idiosyncratic hepatotoxicity and pancreatitis, particularly in younger patients. However, these side effects are more frequent in patients taking valproate as a co-medication with other anticonvulsants. 

Walgren JL, Mitchell MD, Thompson DC. Role of metabolism in drug-induced idiosyncratic hepatotoxicity. Crit Rev Toxicol 2005 35 325-361. 

Shaw PJ, Ditewig AC, Waring JF, et al. Coexposure of mice to trovafloxacin and lipopolysaccharide, a model of idiosyncratic hepatotoxicity, results in a unique gene expression profile and interferon gamma-dependent liver injury. Toxicol Sci. 2009 107(l) 270-280. 

Additional safety concern A time-dependent inhibitor may need to be further studied to define its hepatotoxic potential, as a number of time-dependent P450 inhibitors are found to cause idiosyncratic hepatotoxicity. 

We have tested the ability of covalent binding measurements in predicting idiosyncratic hepatotoxicity by examining the binding of eighteen drugs (nine hepatotoxins and nine nonhepatotoxins) to human hepatic tissue,... 

A rare but potentially fatal idiosyncratic hepatotoxicity can occur with disulfiram. As a result, baseline liver function tests should be obtained and the patient monitored for hepatotoxicity by monitoring for symptoms and by repeating the liver function tests at 2 weeks,... 

Although idiosyncratic hepatotoxicity is a relatively rare event, a number of drugs have the potential of inducing such a toxicity (Table 13.5). 

Drugs Known To Be Associated with Idiosyncratic Hepatotoxicity... 

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