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

本研究的目的是表征糖尿病状态的药代动力学变化。研究了链脲佐菌素诱导的糖尿病大鼠的药物命运。无论吸收特性如何，糖尿病状态下肠道对药物的吸收均增加。肠道吸收增加的原因是肠道黏膜面积增加、刷状缘膜通透性增加和/或肠道黏膜主动运输的载体蛋白增加。以甲苯丁胺为例，在糖尿病状态下肠道吸收增加，但由于肝脏代谢加速，在肠袢给药后的AUC降低。糖尿病状态下药物代谢加速似乎是由于肝脏细胞色素P-450含量增加所致。糖尿病患者血浆白蛋白浓度的降低和红细胞压积的增加均导致非结合药物浓度的增加，特别是与血浆蛋白高度结合的药物。糖尿病大鼠的头孢氨苄消除加速，提示糖尿病状态下尿排泄过程增强。综上所述，在糖尿病状态下，肠道吸收增加的同时，消除过程（肝脏代谢和尿液排泄）加快，导致血浆浓度出乎意料地低。另一方面，由于血浆中白蛋白浓度降低，血浆体积减小，导致蛋白质结合减少，在糖尿病状态下很有可能出现意想不到的副作用。

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.