Mechanisms of idiosyncratic drug reactions: the case of felbamate.
Idiosyncratic drug reactions (IDR) are a specific type of drug toxicity characterized by their delayed onset, low incidence and reactive metabolite formation with little, if any, correlation between pharmacokinetics or pharmacodynamics and the toxicological outcome. As the name implies, IDR are unpredictable and often result in the post marketing failure of otherwise useful therapies. Examples of drugs, which have failed as a result of IDR in recent years, include trovafloxacin, zileuton, troglitazone, tolcapone and felbamate. To date there exists no pre-clinical model to predict these adverse drug reactions and a mechanistic understanding of these toxicities remains limited. In an attempt to better understand this class of drug toxicities and gain mechanistic insight, we have studied the IDR associated with a model compound, felbamate. Our studies with felbamate are consistent with the theory that compounds which cause IDR undergo bioactivation to a highly reactive electrophilic metabolite that is capable of forming covalent protein adducts in vivo. In additon, our data suggest that under normal physiological conditions glutathione plays a protective role in preventing IDR during felbamate therapy, further emphasizing a correlation between reactive metabolite formation and a toxic outcome. Clinical studies with felbamate have been able to demonstrate an association between reactive metabolite formation and a clinically relevant toxicity; however, additional research is required to more fully understand the link between reactive metabolite formation and the events which elicit toxicity. Going forward, it seems reasonable that screening for reactive metabolite formation in early drug discovery may be an important tool in eliminating the post-marketing failure of otherwise useful therapies.
Dieckhaus
Christine M
CM
Merck Research Laboratories, WP75-100, PO Box 4, Sumneytown Pike, West Point, PA 19486-0004, USA. christine_dieckhaus@merck.com
Thompson
Charles D
CD
Roller
Shane G
SG
Macdonald
Timothy L
TL
D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D000927:Anticonvulsants / Q000276:immunology / Q000493:pharmacokinetics / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury; D000078328:Felbamate; D005562:Formazans / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D048448:Phenylcarbamates; D011409:Propylene Glycols / Q000276:immunology / Q000493:pharmacokinetics / Q000633:toxicity*; D013778:Tetrazolium Salts / Q000378:metabolism
D000447:Aldehydes; D000927:Anticonvulsants; D005562:Formazans; D048448:Phenylcarbamates; D011409:Propylene Glycols; D013778:Tetrazolium Salts; C462359:tert-4-hydroxy-2-nonenal; C079782:MTT formazan; D000444:Aldehyde Dehydrogenase; D005982:Glutathione Transferase; D000078328:Felbamate