Experimental Analysis of Anomalous Pharmacokinetics in Disease State: Pharmacokinetics in Diabetes

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The purpose of this study was to characterize the Pharmacokinetic changes in the diabetic state. The fate of drugs was examined in streptozotocin-induced diabetic rats.1. The intestinal absorption of drugs was increased in the diabetic state, regardless of the absorption characteristics.2. The increased intestinal absorption was caused by the increase in the area of the intestinal mucosa, the increase in the permeability of the brush border membrane and/or the increase in the carrier protein for the active transport in the intestinal mucosa.3. In the case of tolbutamide, while the intestinal absorption was increased in the diabetic state, the AUC following the administration in the intestinal loop was decreased due to the acceleration of the metabolism in the liver.4. The accelerated drug metabolism in the diabetic state seemed to be resulted from the increase in cytochrome P-450 content in the liver.5. Both lowered albumin concentration in the diabetic plasma and increased bematocrit resulted in the increase in the concentration of unbound drug, especially in the case of drugs highly bound to plasma protein.6. Elimination of cepbalexin was accelerated in the diabetic rat, suggesting the enhancement of the urinary excretion process in the diabetic state.In conclusion, while the intestinal absorption is increased in the diabetic state, the elimination processes (metabolism in the liver and urinary excretion) are accelerated, resulting in the unexpectedly poor plasma concentration. On the other hand, there is much possibility of the unexpected side effects in the diabetic state due to the decreased protein binding, caused by lowered albumin concentration in the plasma and decreased plasma volume.