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Background and purpose: Glucokinase (GK) is the rate-limiting enzyme of hepatic glucose metabolism and acts as a sensor for glucose-stimulated insulin release in β-cells. Here we examine whether the lowering of blood glucose levels in the rat by small molecule glucokinase activators (GKAs) can be predicted from in vitro enzyme potencies and plasma compound exposure. Experimental approach: We developed an insulin resistant and hyperinsulinemic animal model, the high fat fed female Zucker (fa/fa) rat (HFFZ), and measured the acute in vivo glucose-lowering efficacy of a number of GKAs in an oral glucose tolerance test. Key results: Four GKAs (at 1 to 30 mg kg-1), with different in vitro enzyme potencies, dose-dependently improved oral glucose tolerance in HFFZ rats (10-40% decrease glucose area under the curve (AUC) from vehicle control). The extent of glucose lowering, or the pharmacodynamic (PD) effect, of a GKA was directly related to the total compound concentration in the plasma; the pharmacokinetic (PK) measurement. This PK-PD relationship was extended across a series of GKAs by accounting for differences in protein binding and in the in vitro potency. Conclusions and implications: When the unbound GKA compound level is greater than the in vitro enzyme potency there was significant blood glucose lowering in vivo. This latter relationship was upheld in non-diabetic Wistar rats orally dosed with a GKA. The robust and predictive nature of the PK-PD relationship for GKAs may prove of value in testing these agents in early human clinical studies. [ABSTRACT FROM AUTHOR]