Tissue Distribution and Metabolism of Drugs VI: Effect of Second Drugs on Pancreatic Distribution and Insulin-Releasing Activity of Sulfonylureas in Perfused Rat Pancreas

Abstract

The distribution of sulfonylureas and their insulin-releasing potency as a pharmacological response were studied in isolated perfused rat pancreas. Sulfonylurea concentrations in the perfused pancreas in the presence or absence of a second drug were determined after perfusion for 15min. Sulfonylureas could be distributed throughout the pancreas readily, and the tissue sulfonylurea concentration was reduced by the addition of sulfaphenazole, sulfadimethoxine, and salicylic acid. The insulin secretion rate stimulated by tolbutamide also was reduced by these three drugs; sulfanilamide, which could not displace the tolbutamide distribution, did not affect the tolbutamide-mediated secretion of insulin. These results document the importance of drug concentration in the tissue or receptor site with regard to insulin secretion and show that the sulfonylurea-mediated secretion of insulin can be modified easily by concomitant perfusion of a second drug that displaces sulfonylurea in the pancreas. These findings suggest that the drug interaction at the target organ or receptor site should be understood to provide adequate drug therapy.