tolbutamide + fluconazole

Tolbutamide + fluconazole is a drug combination specifically studied by the University of Minnesota to investigate the impact of CYP2C9 genetic polymorphisms on drug-drug interactions. Tolbutamide is a first-generation sulfonylurea used in the management of Type 2 diabetes; it acts by stimulating insulin secretion from pancreatic beta cells through the antagonism of ATP-sensitive potassium channels. Fluconazole is a triazole antifungal agent primarily used to treat various fungal infections by inhibiting fungal lanosterol 14-alpha-demethylase, which is essential for ergosterol synthesis. In the context of human metabolism, fluconazole is also a potent inhibitor of the hepatic enzyme Cytochrome P450 2C9 (CYP2C9). Because tolbutamide is a substrate for CYP2C9, co-administration with fluconazole can lead to significantly increased plasma concentrations of tolbutamide, thereby increasing the risk of severe hypoglycemia. The University of Minnesota research focused on how different CYP2C9 genotypes (such as *1, *2, and *3 alleles) modulate the magnitude of this interaction in healthy volunteers.