Felbamate‐associated fatal acute hepatic necrosis

OʼNeil, Michael G.; Perdun, Carla S; Wilson, Martin; McGown, Steven T.; Patel, Shyamal

doi:10.1212/wnl.46.5.1457

Cited by 88 publications

(36 citation statements)

References 3 publications

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“…Within the first year of introduction of the antiepileptic drug felbamate, an unexpected association between felbamate therapy and reported cases of aplastic anemia and hepatotoxicity were realized [395][396][397][398][399]. In all, 34 cases of aplastic anemia, resulting in 13 deaths, and 23 cases of hepatic failure, resulting in 5 deaths, were reported to the manufacturer.…”

Section: Mechanismmentioning

confidence: 99%

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Kalgutkar¹,

Gardner²,

Obach³

et al. 2005

CDM

576

507

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The occurrence of idiosyncratic adverse drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use and even in its withdrawal. Metabolic activation of relatively inert functional groups to reactive electrophilic intermediates is considered to be an obligatory event in the etiology of many drug-induced adverse reactions. Therefore, a thorough examination of the biochemical reactivity of functional groups/structural motifs in all new drug candidates is essential from a safety standpoint. A major theme attempted in this review is the comprehensive cataloging of all of the known bioactivation pathways of functional groups or structural motifs commonly utilized in drug design efforts. Potential strategies in the detection of reactive intermediates in biochemical systems are also discussed. The intention of this review is not to "black list" functional groups or to immediately discard compounds based on their potential to form reactive metabolites, but rather to serve as a resource describing the structural diversity of these functionalities as well as experimental approaches that could be taken to evaluate whether a "structural alert" in a new drug candidate undergoes bioactivation to reactive metabolites.

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Section: Mechanismmentioning

confidence: 99%

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Kalgutkar¹,

Gardner²,

Obach³

et al. 2005

CDM

576

507

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show abstract

“…In its first year of approval, between 100,000 and 125,000 patients were given FBM therapy in the United States. However, within the first year of widespread use, adverse reactions were reported, notably aplastic anemia and hepatotoxicity (5,6). The severity and frequency of occurrence of these side effects prompted a recommendation by the Food and Drug Administration (FDA) in August I994 to Accepted November 16,1998.…”

mentioning

confidence: 99%

Quantification in Patient Urine Samples of Felbamate and Three Metabolites: Acid Carbamate and Two Mercapturic Acids

et al. 1999

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Summary:Purpose: Previously we proposed and provided evidence for the metabolic pathway of felbamate (FBM), which leads to the reactive metabolite, 3-carbamoyl-2-phenylpropionaldehyde. This aldehyde carbamate was suggested to be the reactive intermediate in the oxidation of 2-phenyl-1,3-propanediol monocarbamate to the major human metabolite 3-carbamoyl-2-phenylpropionic acid. In addition, the aldehyde carbamate was found to undergo spontaneous elimination to 2-phenylpropenal, commonly known as atropaldehyde. Moreover, atropaldehyde was proposed to play a role in the development of toxicity during FBM therapy. Evidence for atropaldehyde formation in vivo was reported with the identification of modified N-acetyl-cysteine conjugates of atropaldehyde in both human and rat urine after FBM administration. Identification of the atropaldehyde-derived mercapturic acids in urine after FBM administration is consistent with the hypothesis that atropaldehyde is formed in vivo and that it reacts with thiol nucleophiles. Based on the hypothesis that the potential for toxicity will correlate to the amount of atropaldehyde formed, we sought to develop an analytic method that would quantify the amount of relevant metabolites excreted in patient urine.Methods: We summarize the results of an LClMS method used to quantify FBM, 3-carbamoyl-2-phenylpropionic acid and two atropaldehyde-derived mercapturic acids in the patient population.Results: Analysis was performed on 3 I patients undergoing FBM therapy. The absolute quantities of FBM and three metabolites were measured.Conclusions: This method demonstrated sufficient precision for the identification of patients exhibiting "abnormal" levels of atropaldehyde conjugates and may hold potential for patient monitoring.

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“…Felbamate (2-phenyl-1,3-propanediol dicarbamate) is an antiepileptic drug (AED) whose use has been restricted because of hepatotoxicity and aplastic anemia [11,197]. In contrast to humans, felbamate is essentially nontoxic in animals (i.e., rat, dog, and monkey) even at high doses [80].…”

Section: Felbamate-induced Liver Toxicity and Aplastic Anemiamentioning

confidence: 99%

Idiosyncratic Drug Reactions

Wojcinski

Uetrecht

2012

Encyclopedia of Drug Metabolism and Interactions

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Idiosyncratic drug reactions (IDRs) are adverse drug reactions that are not related to the known pharmacological properties of the drug occur in only a small percentage of the population and do not show any apparent dose–response relationship. The unpredictable nature of IDRs together with the often serious adverse effects encountered pose a major health concern in the development and clinical usage of pharmaceuticals. The mechanism of IDRs is not clearly understood, and although several theories have been proposed, IDRs can be generally categorized mechanistically as either immune mediated or non‐immune‐mediated. There is circumstantial evidence that suggests that most idiosyncratic reactions are hypersensitivity reactions initiated by the formation of chemically reactive metabolites that bind to proteins and induce an immune‐mediated response. Investigations in animal models have had limited success owing to the unpredictability of IDRs in animals, which is similar to the situation in humans. However, IDRs in animals do share some similar characteristics and mechanisms observed in humans supporting the need for further study of animal models.

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Felbamate‐associated fatal acute hepatic necrosis

Cited by 88 publications

References 3 publications

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Quantification in Patient Urine Samples of Felbamate and Three Metabolites: Acid Carbamate and Two Mercapturic Acids

Idiosyncratic Drug Reactions

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