Tolbutamide is used increasingly as an investigative tool in in vivo studies of the physiology of glucose tolerance. Its hypoglycemic effect in nondiabetic subjects is widely variable, reflecting possible variability in its pharmacokinetics, an insulinergic response, an extrapancreatic effect of the drug, or the hypoglycemic effect of insulin itself. Using population-based modeling, we have investigated the kinetics and dynamics of tolbutamide and assessed covariates in two groups of healthy subjects. The results indicate a high variability in insulinergic effect, measured by the area under of the curve of insulin (0-60 min), in response to tolbutamide injection (coefficient of variation = 29-96%). However, it appears that impaired insulin sensitivity is compensated by higher insulin secretion in response to tolbutamide. Thus the hypoglycemic effect of high insulin secretion is minimal in insulin-resistant subjects. Application of the model indicated that tolbutamide has appreciable extrapancreatic effects mediated by prolongation of the residence time of insulin in a remote effect and by enhancement of glucose effectiveness. An effect in increasing the insulin sensitivity index is also possible but could not be confirmed statistically for all groups of subjects studied. These observations may explain inconsistencies between the results of tolbutamide and insulin injection in the frequently sampled intravenous glucose tolerance test and call for further study of insulin- vs. tolbutamide-modified frequently sampled intravenous glucose tolerance tests in the assessment of the insulin sensitivity and glucose effectiveness indexes.