非類固醇抗發炎藥、茶及番瀉葉對腎毒素血中濃度之影響及機轉

• Main Authors: Yu-Hsuan Peng, 彭禹璇
• Other Authors: Pei-Dawn Lee Chao
• Format: Others
• Language: zh-TW
• Published: 2016
• Online Access: http://ndltd.ncl.edu.tw/handle/80860376031654773102

博士 === 中國醫藥大學 === 藥學系博士班 === 104 === Chronic kidney disease (CKD) is a major health problem worldwide. Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are highly protein-bound and cannot be efficiently removed through hemodialysis. The elevated serum levels of IS and PCS were associated with the progression of CKD and cardiovascular diseases (CVD) as well as all-cause mortality. Because of the acidic properties, IS and PCS are existing as anions under physiological pH in the systemic circulation, and the transport and excretion of IS and PCS were mediated by organic anion transporters such as organic anion transporter (OAT) 1 and OAT3. Because the major molecules in the bloodstream after dosing non-steroidal anti-inflammatory drugs (NSAIDs), teas and Folium Sennae were anions, we hypothesized that they might compete with IS and PCS for the same transporters. Therefore, this study aimed to investigate the effects of NSAIDs, teas and Folium Sennae on the serum levels of IS and PCS. First, rats were injected an intravenous bolus of IS alone and with tested agents to evaluate the effects on the elimination of IS. Secondly, a chronic renal failure (CRF) rat model was established to investigate the effect of green tea (GT) on the serum levels of endogenous IS and PCS and the renal function. Furthermore, cell models were used to verify the involvement of individual transporters in the mechanism. The results showed that ketoprofen and diclofenac decreased the clearance of IS and increased its kidney concentration through inhibition on the uptake transport mediated by OAT1 and OAT3, as well as the apical efflux transporters. GT ingestion decreased the clearance of IS, and increased the serum levels of endogenous IS and PCS as well as Cr and BUN in CRF rats. Mechanism studies indicated that the serum metabolites of GT inhibited the uptake transport of IS and PCS mediated by OAT1 and OAT3. Conversely, Folium Sennae increased the systemic clearance of IS. In conclusion, NSAIDs and GT hampered the elimination of IS through inhibition on OAT1 and OAT3. GT increased the serum levels of endogenous IS and PCS, and deteriorated the kidney function of CRF rats. This information would be valuable for the clinical professionals and CKD patients to delay the progression of CKD and CVD.