Sulfonylureas can Stimulate Insulin Release by Flip-Flop across Phospholipid Membranes

The design of new drugs and drug-delivery systems requires insight about how a drug interacts with the phospholipid bilayer. Sulfonylureas are used to treat type 2 diabetes mellitus because they stimulate insulin secretion from pancreatic β-cells. Two generations of Sulfonylurea drugs have been marketed to treat type II diabetes mellitus. Tolbutamide was chosen to represent the first generation of these drugs, whereas Glibenclamide was from the second generation. This study investigated how the Sulfonylureas cross the phospholipid membrane and it found that these drugs are transported by non-energy dependent flip-flop mechanism. A u-shaped conformation for both Tolbutamide and Glibenclamide is being proposed to explain the binding of these drugs to the phospholipid membrane.