Sulfonylureas were developed over 50 years ago and the first-generation agents, such as tolbutamide, chlorpropamide, and tolazamide, have a lower potency than the second-generation agents (glipizide, glibenclamide/gliburide, gliclazide, glisoxepide) (4). Potency correlates quite well with the affinity for the sulfonylurea receptor, and second-generation agents have a higher affinity for the sulfonylurea receptor. Glimepiride was proposed to possess some extrapancreatic effects and has therefore been termed a third-generation agent. However, with the development of a wide range of different sulfonylureas and meglitinides, the classification into different generations is more a marketing aspect than a meaningful characterization. The pharmacokinetic properties are summarized in Table 1.
The meglitinides differ structurally from the sulfonylureas and do not contain the sulfonylurea chemical motif. Repaglinide is a benzoic acid derivative, and nateglinide is derived from the amino acid tryptophane. Both compounds have substantially shorter duration of action than glibenclamide or glimepiride and have no active metabolites.
All these compounds bind to the sulfonylurea receptor and share the mechanism of action, i.e., all close the ATP-dependent potassium channel. The exact binding sites may differ somewhat, leading to complex displacement curves of radiolabeled glibenclamide (12), but the clinical significance of such rather subtle differences is unclear. Nateglinide has low affinity for the ATP-dependent potassium channel and, therefore, has rapid kinetics of association and dissociation, while repaglinide is intermediate between the high-affinity ligands glibenclamide or glimepiride and nateglinide.
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