The Inhibitory Effect of the Second Generation Sulfonylurea Drugs on Cytochrome P450-catalyzed Reaction by Human Liver Microsomes.

Background: Sulfonylurea drugs have been used for many decades as one of the main families of drugs for the treatment of type 2 diabetes mellitus. Even though there are many opportunities to medicate sulfonylurea drugs concomitantly with many other drugs, and furthermore there have been several case reports on drug interactions with sulfonylurea drugs, there has been no clear demonstration revealing the mechanisms that cause these interactions. We therefore evaluated inhibitory potential of sulfonylurea drugs, including glibenclamide, glipizide and gliclazide, on the cytochrome P450 (CYP)-catalyzing enzymes using human liver microsomes. Methods: The inhibitory effects of glibenclamide, glipizide and gliclazide, on the CYP-catalyzing reaction, were evaluated for CYPIA2, CYP2C9, CYP2C I9, CYP2D6 and CYP3A4 using human liver microsomes, and probe drugs for each. Results: Glibenclamide showed relative potent inhibitory effects on the CYP2C9- and CYP3A4-catallyzed reaction (; 11.3 (M and 59.0 (.M). The other CYP isoforms tested showed only weak inhibitory effects by due to glibenclamide (> 112 (.M). Glipizide showed potent inhibitory effect on CYP3A4-catalyzed reaction only (; 11.2 (.M), and weak, or no, inhibitory effects on each on the other CYP isoforms tested ( > 276 (M). Conclusion: The sulfonylurea drugs showed inhibitory potential on the CYP-catalyzing reaction in human liver microsomes. The results obtained in the present study provide insights into the potential of the drug interaction to ward drugs co-administered with sulfonylureas. It will be necessary to take into consideration the control of blood glucose, as well as therapeutic drug monitoring, to reduced toxicities when sulfonylurea drugs are co-administered with drugs of a narrow therapeutic range, or with severe dose-dependent toxicities.