Biological Activities of Tolbutamide and Its Metabolites: A Dissociation of Insulin-releasing and Hypoglycemic Activity

Studies carried out with intact and adrenalectomized mice have demonstrated that modification of the tolbutamide molecule causes a dissociation between its insulinreleasing and hypoglycemic activity. Although tolbutamide and hydroxymethyltolbutamide have the same insulin-releasing effect, hydroxymethyltolbutamide has only 35 per cent of the hypoglycemic potency of tolbutamide. Carboxytolbutamide is devoid of hypoglycemic potency despite a definite, but weaker, insulin-releasing action when compared to tolbutamide. Carboxytolbutamide's insulin-releasing activity was confirmed in in vitro studies with golden hamster pancreas. Thus, insulin release is not the only factor involved in the acute hypoglycemic action of sulfonylureas and, indeed, may not even be the major factor.