Effect of experimental diabetes on drug metabolism in the rat

The effect of experimental diabetes on hepatic drug metabolism was studied in male Holtzman rats. Treatment of animals with streptozotocin and 6-aminonicotinamide, both agents which produce an insulin-deficient animal, caused prolongation of hexobarbital sleeping times and inhibition of the rate of metabolism of both hexobarbital and, to a lesser extent, aniline in vitro. Treatment of animals with N-methylacetamide, a diabetogen which does not cause insulin deficiency in the animal but rather produces an insulin-resistant state, did not affect the metabolism in vitro of either hexobarbital or aniline. Neither insulin nor any of the diabetogenic agents had any direct effect on drug metabolism in vitro. Furthermore, hepatic microsomal protein and cytochrome P-450 contents were not significantly different in any of the diabetic animals from those of the control animals. Hyperglycemia produced by glucose infusion did not affect the metabolism of hexobarbital in vitro. The effects of streptozotocin and 6-aminonicotinamide appeared to be at least partially due to the presence of an inhibitor in the liver cytosol which correlated with elevated hepatic cyclic AMP concentrations.