Learning to use troglitazone.

CONTEXT: Soon after initial marketing in March 1997, troglitazone, the first thiazolidinedione antidiabetic agent, was found to cause life-threatening acute liver failure. The drug was removed from the market in March 2000. OBJECTIVE: To evaluate the effect of US Food and Drug Administration (FDA) risk management efforts, including repeated labeling changes and "Dear Healthcare Professional" letters, on periodic liver enzyme monitoring of patients taking troglitazone. DESIGN, SETTING, AND PARTICIPANTS: Claims data from a large, multistate managed care organization were used to establish 4 cohorts of patients (N = 7603) with at least 90 days of health plan enrollment before first troglitazone prescription during 4 consecutive periods spanning April 1997 to September 1999 and representing 4 progressively stringent liver monitoring recommendations. MAIN OUTCOME MEASURES: Percentage of eligible troglitazone users in each cohort with baseline, monthly (for up to 6 months of continuous use), and complete (baseline and monthly) enzyme monitoring, based on computerized records of laboratory claims. RESULTS: Baseline testing increased from 15% before any FDA monitoring recommendations (cohort 1) to 44.6% following 4 separate FDA interventions (cohort 4; P<.001). In cohort 4, 33.4% of users had follow-up testing after 1 month of therapy, falling to 13% after 5 months of continuous use. In all cohorts, less than 5% received all recommended liver enzyme tests by the third month of continuous use. CONCLUSIONS: The FDA risk management efforts did not achieve meaningful or sustained improvement in liver enzyme testing. Evaluation of the impact of regulatory actions is needed before such actions can be regarded as effective or sufficient.

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PubMed2001

Inhibitory effect of troglitazone on glucuronidation catalyzed by human uridine diphosphate-glucuronosyltransferase 1A6.

OBJECTIVE: Troglitazone is a useful new thiazolidinedione oral antidiabetic agent, but it is unpredictably hepatotoxic in about 1.9% of patients. In vitro studies of drug interactions are important in understanding the basis for the pharmacological and toxicological actions of drugs. In the present study, we investigated whether troglitazone inhibits uridine diphosphate (UDP)-glucuronosyltransferase 1A6 (UGT1A6) activity. METHODS: Human cDNA-expressed UGT1A6 was coincubated with troglitazone (inhibitor) and 1-naphthol (substrate). The glucuronidation of 1-naphthol was determined to establish a 50% inhibitory concentration (IC50) and an inhibition (Ki) value. RESULTS: Troglitazone inhibited UGT1A6 activity with an IC50 of 28 microM at a 1-naphthol concentration of 20 microM. The inhibition was a mixed-type mechanism with a Ki value of 20 microM. CONCLUSION: Inhibitory effect of troglitazone is weak, however, co-administration of troglitazone might carry a drug concentration into the toxic range when the concentration approaches a threshold of toxicity by an inherent reduction of UGT1A6 activity.

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