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

疾病状态下异常药代动力学的实验分析：糖尿病的药代动力学

• 批准号: 63571097
• 负责人: KIMURA Toshikiro
• 金额: $ 1.34万
• 依托单位: Okayama University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1988
• 资助国家: 日本
• 起止时间: 1988 至 1989
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-63571097/
• 关键词: Diabetes; Streptozotocin; Drug absorption; Drug metabolism; Urinary excretion; Plasma protein binding; streptozotocin

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.

本研究的目的是表征糖尿病状态下的药代动力学变化。在链脲佐菌素诱导的糖尿病大鼠中检查了药物的命运。 1．无论吸收特性如何，糖尿病状态下药物的肠道吸收均增加。2．肠道吸收增加是由于肠粘膜面积增加、刷状缘膜通透性增加和/或肠粘膜主动转运的载体蛋白增加所致。3．就甲苯磺丁脲而言，虽然糖尿病状态下肠道吸收增加，但由于肝脏代谢加速，肠循环给药后的AUC降低。4．糖尿病状态下药物代谢加速可能是由于肝脏细胞色素P-450含量增加所致。 5．糖尿病血浆中白蛋白浓度降低和血细胞比容增加均导致未结合药物浓度增加，尤其是与血浆蛋白高度结合的药物。6．糖尿病大鼠中头孢氨苄的消除加速，表明糖尿病状态下尿排泄过程增强。 总之，糖尿病状态下肠道吸收增加，消除过程（肝脏代谢和尿排泄）较慢。加速，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和血浆容量减少导致蛋白质结合减少，因此在糖尿病状态下很可能出现意想不到的副作用。