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 co-incubated 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 µM at a 1-naphthol concentration of 20 µM. The inhibition was a mixed-type mechanism with a Ki value of 20 µM. 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.