Investigation of drug transport function through biological membranes and physiological role in endotoxemia

点击翻译按钮获取中文摘要

Results obtained from this research are represented as follows :1. The involvement of cytokines and mediators, such TNF-α, IL-1 and PAF, in endotoxin-induced decreases in the content of CYP and protein levels of CYP3A2 and 2C11 appears to be small.2. Some quinolone antimicrobial agents increased the intracellular accumulation of doxorubicin, a substrate of P-glycoprotein, in P-glycoprotein-dependent anticancer drug resistant cells, suggesting that they can reverse anticancer drug resistance of tumors. They are excreted into the bile by a P-glycoprotein-mediated transport system.3. Endotoxin did not change the activity of glucuronidation, but decreased sparfloxacin and its glucuronide due to impairment of Mrp2- and/or P-glycoprotein-mediated hepatobiliary transport systems and renal handling.4. The expression of Mdrla mRNA in both liver and kidney decreased 6 h after endotoxin injection and returned to control level. Endotoxin decreased P-glycoprotein-mediated biliary and renal excretion of rhodamine-123 by decreasing the expression of Mdrla, which is likely due to increased plasma TNF-α levels.5. Endotoxin did not induce histopathological changes in the brain capillaries, and had no effect on the brain capillary integrity and doxorubicin transport across the blood-brain barrier (BBB) in mice. Endotoxin did not change the function and expression of P-glycoprotein in the brain. It is likely that P-glycoprotein function might be sufficient to transport doxorubicin despite of decreased levels of P-glycoprotein in the brain.6. Shiga-like toxin II impairs the BBB function and doxorubicin transport across the BBB, while induces upregulation of P-glycoprotein, which are different from results by endotoxin injection. The discrepancy between endotoxin and Shiga-like toxin II may be explained by the difference in the contents of cytokine production.