Kinetics-effect relations of glipizide and other sulfonylureas.

The kinetics-effect relations of glipizide (Gz), glibenclamide (Gb), tolbutamide (Tb) and chlorpropamide (Cp) were studied in diabetics and healthy volunteers, by gas chromatographic (Tb, Cp), high-pressure liquid chromatographic (Gz), radioimmunologic (Gb, insulin) and enzymatic (glucose) analyses. For each of the four drugs, the steady state concentrations showed very large between-patient variations, not attributable to dosage or weight differences but to individual differences in drug kinetics and to insufficient compliance. Single-dose comparisons in healthy volunteers showed that Gz and Gb are much more potent than Tb and Cp, and suggested that Gz is the most rapid-acting one. Food did not affect the bioavailability of any of the four drugs, but delayed Gz absorption. Both Gz and Gb yielded better blood glucose reductions when given 30 minutes before, than together with, meals. Each drug could evoke glucose reduction without enhancing peripheral insulin levels; this probably reflects extrapancreatic sulfonylurea effects. In conclusion, it appears that a) the dosage of each sulfonylurea must be individualized, b) Gz and Gb are much more potent than Tb and Cp, c) Gz has the most favourable therapeutic profile as it seems to be the most rapid- and short-acting of the four sulfonylureas. d) Gz and Gb should be given before rather than together with, meals, in order to obtain optimal effects.