腎臟有機陰離子運輸蛋白担體I於家兔體內藥物交互作用之藥物動力學研究

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題名:	腎臟有機陰離子運輸蛋白担體I於家兔體內藥物交互作用之藥物動力學研究 Pharmacokinetic Studies of Drug-Drug Interactions by Renal Organic Anion Transporter I in Rabbits
作者:	陳韻安 Yun-An Chen
貢獻者:	藥學研究所
關鍵詞:	有機陰離子運輸蛋白担體I 對胺馬尿酸異丁苯乙酸引朵美洒辛 organic anion transporter I p-aminohippuric acid indomethacin ibuprofen
日期:	2009
上傳時間:	2009-09-15 15:49:18 (UTC+8)
摘要:	運輸蛋白(transporter)是一種在細胞膜上掌控物質進出的蛋白質，近年來許多臨床上發生的藥物交互作用被認為可能與其有關。本實驗的目的為以單劑量與多劑量兩種不同的合併給藥方式來探討兔子腎臟上有機陰離子運輸蛋白担體I(Organic anion transporter I, OATI)進行交互作用時的藥物動力學變化本實驗藥物p-Aminohippuric acid (PAH)、Ibuprofen (IBU)及Indomethacin (INDO)在血漿中濃度的分析方法皆採用逆向高效液相層析法，其血中濃度檢量線在本實驗濃度範圍內具有良好的線性關係以及準確性與精確性。口服同莫耳單一劑量的IBU(21.38mg/kg)或INDO(37.08mg/kg)至家兔體內，並同時靜脈注射等莫耳數之PAH(20mg/kg)，可得單劑量給藥後結果。實驗顯示：(1) INDO血中濃度曲線下面積(AUC)及最高血中濃度(Cmax)相較於對照組有8.42至11.33倍顯著差異(p<0.01)；清除率(clearance,CL)有6.94倍的顯著下降(p<0.01)。(2) PAH之AUC及CL有稍微上升及下降。(3) IBU的AUC稍微上升且CL下降了3.56倍(p<0.01)。(4) PAH在與IBU單劑量合併使用時，AUC些微上升。多劑量IBU或INDO口服給藥後發現：(1) INDO的AUC及Cmax有15.02至20.93倍之顯著上升(p<0.01)；CL下降了19.66倍(p<0.01)。(2) PAH與INDO合併給藥時，其AUC有2.07倍的顯著上升(p<0.01)；CL有1.94倍的顯著下降(p<0.01)。(3) IBU的AUC上升且CL下降了5.53倍(p<0.01)。(4) PAH在與IBU多劑量合併使用時，AUC及CL都有上升及下降。INDO經由腎排除的比例有60%，IBU則約45%~75%，但因IBU在腎小管的主動分泌比例只有約1%，而INDO則將近34.4%，故在評估OATI對於IBU與INDO的影響時須考慮此因素。由實驗結果可知，OATI上發生藥物交互作用時會改變藥物彼此間的排除。 Carrier-mediated processes, often referred to as transporters which located on the membrane, play key roles in the reabsorption and secretion of many endogenous and xenobiotic compounds by the kidney. In recent years, the specific roles of such transporters in drug disposition and drug-drug interactions become more important. The purpose of this study is to estimate the interaction of drugs with the organic anion transporter I (OATI) in the kidney. An accuracy, precision, simple and specific HPLC method was developed to detect the concentration of p-aminohippuric acid (PAH), ibuprofen (IBU) and indomethacin (INDO) in plasma. The drug-drug interaction evaluating of OATI was determined by combining dosing with same molar dose of I.V. of PAH (20mg/kg) and P.O. administration of single or multiple dose of IBU (21.38mg/kg) and INDO (37.08mg/kg) to rabbits. During single dose of INDO or IBU administration, the results were shown below: (1) INDO: significantly increased the AUC and Cmax by 8.42 to 11.33 fold (p<0.01) and decreased the CL by 6.94 fold (p<0.01). (2) PAH: slightly increased the AUC and slightly decreased the CL. (3) IBU: slightly increased the AUC and Cmax but significantly decreased the CL by 3.56 fold (p<0.01). (4) PAH: combination dosing with IBU slightly increased the AUC. In multiple dose studies, the results were shown below: (1) INDO: significantly increased the AUC and Cmax by 15.02 to 20.93 fold (p<0.01) and decreased the CL by 19.66 fold (p<0.01). (2) PAH: significantly increased the AUC by 2.07 fold (p<0.01) and decreased the CL by 1.94 fold (p<0.01). (3) IBU: slightly increased the AUC and Cmax but significantly decreased the CL by 5.53 fold (p<0.01). (4) PAH: slightly increased the AUC and slightly decreased the CL. The excretion of IBU in kidney (45%-75%) is equal with INDO (60%), but the tubular excretion of IBU was only 1% compared with 34.4% of INDO.This may result the difference of OATI effect. In comparison between single and multiple dose administration, the results showed the higher competition level in drug-drug interaction when INDO or IBU multiple administration. The OATI effect the elimination of IBU and INDO.
資料類型:	thesis
顯示於類別:	[藥學系] 博碩士論文

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