Hepatic Effects of Chlorpropamide: Inhibition of Glucagon-stimulated Gluconeogenesis in Perfused Livers of Fasted Rats

In perfused livers of rats fasted for 24 h, glucagon (5 × 10⁻¹⁰ M) significantly elevated tissue and perfusate levels of cyclic AMP and caused a twofold increase in glucose formation from lactate. Chlorpropamide (0.8 × 10⁻³ M) consistently blocked these effects. Measurements of metabolic intermediates suggest that chlorpropamide may inhibit gluconeogenesis by antagonizing the action of glucagon on the phosphoenolpyruvate cycle.

In the experiments described, chlorpropamide did not lower hepatic ATP concentration or energy charge, and exerted its effects at perfusate concentrations comparable to serum concentrations reported in patients on maintenance doses of the drug.