DIFFERENTIAL INTERACTION OF GLIMEPIRIDE AND GLIBENCLAMIDE WITH THE BETA-CELL SULFONYLUREA RECEPTOR .1. BINDING CHARACTERISTICS

Glimepiride is a novel sulfonylurea drug for treatment of non-insulin- dependent diabetes mellitus with higher blood sugar lowering efficacy in diabetic patients than glibenclamide raising the question whether t his characteristics is in line with different binding of glimepiride a nd glibenclamide to the beta-cell sulfonylurea receptor. Scatchard plo t analysis of [H-3]sulfonylurea binding to membranes isolated from rat beta-cell tumors and (RINm5F) insulinoma cells and to RINm5F cells de monstrated that glimepiride has a 2.5-3-fold lower affinity than glibe nclamide. This corresponded well to the 8-9-fold higher k(off) and 2.5 -3-fold higher k(on) rates of glimepiride compared to glibenclamide as revealed by the dissociation and association kinetics of [H-3]sulfony lurea binding and the K-d values calculated thereof. In agreement, the concentrations required for half-maximal displacement of [H-3]sulfony lurea bound to beta-cell membranes were significantly higher for glime piride compared to glibenclamide. However, the binding affinity of gli mepiride measured by both equilibrium binding and kinetic binding stud ies upon solubilization of beta-cell tumor membranes and RINm5F cell m embranes increased up to the value for glibenclamide. This was primari ly based on a drastic decrease of the dissociation rate constant of gl imepiride whereas the kinetics of glibenclamide binding remained large ly unaffected upon solubilization. These data suggest that the K-d val ue alone is not sufficient for characterization of a sulfonylurea drug , since the kinetic binding parameters may also determine its acute bl ood sugar lowering efficacy.