Study of failed drug troglitazone could explain idiosyncratic drug toxicity

Scientists have advanced the study of trapping reactive metabolites in a move they say could be significant in developing safer drugs.

Preclinical contract research organization Absorption Systems studied the metabolism of troglitazone, a drug that was once indicated for type 2 diabetes but was withdrawn from the market by Japan’s Sankyo in 2000 due to numerous cases of liver failure ( The Pharma Letter March 31 2000). It was also suspended by then Glaxo Wellcome in 1997.

Reactive metabolites of troglitazone had been described previously and could be responsible, at least in part, for the liver toxicity observed in many patients who took the drug before its withdrawal. Because of their transient nature and the fact that they are often present at low levels, reactive metabolites are generally identified indirectly, by capture (trapping) with a reducing agent such as glutathione. Then the structure of the metabolite is elucidated by determining the structure of its glutathione conjugate.