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.


CONCLUSIONS
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.
Ito
M
M
Second Department of Internal Medicine, Department of Biology, Shiga University of Medical Science, Shiga, Japan.
Yamamoto
K
K
Sato
H
H
Fujiyama
Y
Y
Bamba
T
T
D002839:Chromans / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D009284:Naphthols / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone
D002839:Chromans; D007004:Hypoglycemic Agents; D009284:Naphthols; D013844:Thiazoles; D045162:Thiazolidinediones; C029350:1-naphthol; D014453:Glucuronosyltransferase; D000077288:Troglitazone