腎臟有機陰離子運輸蛋白1於家兔體內給予藥物交互作用之藥物動力學研究

Pharmacokinetics studies of drug-drug interactions on renal organic anion transporter 1 in rabbits

賴麒開(Chi-Kai Lai)

指導教授 ： 許光陽

臺北醫學大學/藥學院/藥學研究所/碩士(2011年)

摘要

Indomethacin(INDO)與Ketoprofen(KETO)為非類固醇類抗發炎藥廣泛地利用在各種炎症的緩解與治療，在臨床上陸續發現其與藥物間的交互作用，以及在體外實驗中，發現其與有機陰離子運輸蛋白1（Organic anion transporter 1; OAT1）間的交互作用有關，p-Aminohippuric acid（PAH）為測量腎小管主動分泌的指標物質，且其對腎臟上OAT1具有高度的親和力與專一性，本實驗以靜脈注射的方式分別投予INDO、KETO至紐西蘭大白兔體內，並同時靜脈注射投予同莫耳數的PAH，以探討INDO以及KETO與PAH間藥物動力學上的變化，藉以瞭解其與OAT1之間的交互作用，並更進一步投予多劑量INDO與KETO，使其血中濃度達穩定狀態，分別討論其不同藥物動力學情況下的變化。
本實驗所得到的檢體經前處理後，以逆向高效液相層析法進行分析，其血中濃度的檢定，在濃度範圍內皆具有良好的線性關係、準確度以及精密度。單一劑量的KETO、INDO、PAH分別單獨給予至家兔體內，已觀察其個別的藥物動力學，隨後進行合併給藥實驗，合併給予單一劑量的INDO及PAH或是KETO及PAH，再進行多劑量投予INDO或是KETO，待其血中濃度達穩定狀態後，同時給予單一劑量的PAH加上KETO或是INDO；所得到的檢體經分析後，將血中濃度經計算所得到的藥物動力學參數，進行統計分析，結果顯示在合併給予單一劑量KETO時，兩者的藥物動力學參數皆有所變化，且在KETO血中濃度達到穩定狀態時，其變化更加明顯，PAH的總清除率（clearance; CL）下降（穩定狀態10.0 ± 1.9 vs 單一劑量11.5 ± 控制組0.8 vs 16.8 ± 1.8 mL/min/kg; p < 0.01），排除半衰期延長（117.2 ± 32.1 vs 86.0 ± 12.1 vs 54.4 ± 27.1 min; p < 0.03），KETO的CL也下降（61.4 ± 5.8 vs 74.6 ± 8.7 vs 166.3 ± 18.5 mL/min/kg; p < 0.01），且排除半衰期也有延長（315.0 ± 81.0 vs 423.2 ± 100.3 vs 154.7 ± 31.3 min; p < 0.02），且兩者其他藥物動力學參數也有變化，並具統計學上意義；而在合併給予INDO下，兩者的藥物動力學也產生變化，且在INDO達到穩定狀態下，其變化愈加顯著，PAH的CL下降（6.8 ± 0.8 vs 10.0 ± 1.9 vs 16.8 ± 1.8 mL/min/kg; p< 0.01），排除半衰期延長（188.5 ± 51.9 vs 123.7 ± 23.9 vs 54.4 ± 27.1 min; p < 0.02），而INDO的CL下降（27.2 ± 2.5 vs 56.3 ± 3.6 vs 128.2 ± 12.4 mL/min/kg; p < 0.01），排除半衰期延長（912.8 ± 98.0 vs 825.8 ± 141.7 vs 229.1 ± 76.4 min; p < 0.01），兩者的其他藥物動力學參數與控制組相比，皆有統計學上之明顯差異，以上統計結果，顯示在合併給藥下，PAH、KETO、INDO會互相影響彼此的藥物動力學，進一步以公式計算其個別的淨分泌清除率，可以發現在合併給藥下，PAH的主動分泌清除率下降（合併給予KETO：3.1 ± 1.7 vs 4.4 ± 0.7 vs 9.2 ± 1.6 mL/min/kg; p < 0.05；合併給予INDO：0.2 ± 0.7 vs 3.0 ± 1.2 vs 9.2 ± 1.6 mL/min/kg; p < 0.05），而KETO（43.0 ± 4.3 vs 55.2 ± 17.6 vs 123.5 ± 37.7 mL/min/kg; p < 0.05）及INDO（10.2 ± 1.5 vs 27.4 ± 5.4 vs 70.1 ± 18.3 mL/min/kg; p < 0.05）也有相同的情形，可以推論PAH與INDO及KETO在家兔腎臟上的OAT1發生競爭的情形，而導致其藥物動力學上的變化，這樣的實驗結果也與文獻中細胞實驗的結果有相似的情形。

關鍵字

藥物動力學,家兔,運輸蛋白,藥物交互作用

並列摘要

INDO and KETO are members of the non-steroidal anti-inflamma-tory drugs which are prescribe for the relief and treatment for different inflammatory syndromes. However, the interactions with other drugs and the interactions with organic anion transporter 1 (OAT1) were discovered in vivo and in vitro, respectively. This research wouLd demonstrate the experiment in New Zealand rabbits via administration of INDO or KETO which wouLd help understanding the relationship between the OAT1 and INDO or KETO and the effects on pharmacokinetic.
p-Aminohippuric acid (PAH) is the index compound for estimating the active excretion of the proximal tubule, and highly specific to OAT1. We administrated PAH intravenously with or without INDO or KETO as the same mole as PAH contemporarily. We could explore the interaction between INDO, KETO, PAH and OAT1 via observing the variation on pharmacokinetic parameters.
A simple HPLC-based method with good linearity, accuracy and precision was developed for detecting the concentration of INDO, KETO and PAH in rabbit plasma. First, single-dose of PAH, KETO and INDO were administrated to rabbits for determining their pharmacokinetic(PK) parameters as control, and the following data was collected for comparison to the control. Second, a single-dose of PAH was administrated with a single-dose of KETO or INDO simultaneously, separately. Third, the KETO and INDO were administrated as multiple dosing for reaching steady state. Then a single-dose of PAH was administrated with a single-dose of KETO or INDO simultaneously, separately. After co-administrated with KETO, compared to control, the clearance(CL) of PAH decreased(steady state: 10.0 ± 1.9 vs single-dose: 11.5 ± control: 0.8 vs 16.8 ± 1.8 mL/min/kg; p < 0.01), and the elimination half-life prolonged(117.2 ± 32.1 vs 86.0 ± 12.1 vs 54.4 ± 27.1 min; p < 0.03), also the CL of KETO decreased(61.4 ± 5.8 vs 74.6 ± 8.7 vs 166.3 ± 18.5 mL/min/kg; p < 0.01), and the elimination half-life prolonged(315.0 ± 81.0 vs 423.2 ± 100.3 vs 154.7 ± 31.3 min; p < 0.02). Other PK parameters were also changed with statistically significants. After administrated with INDO, the clearance(CL) of PAH decreased(6.8 ± 0.8 vs 10.0 ± 1.9 vs 16.8 ± 1.8 mL/min/kg; p< 0.01), and the elimination half-life prolonged(188.5 ± 51.9 vs 123.7 ± 23.9 vs 54.4 ± 27.1 min; p < 0.02), also the CL of KETO decreased(27.2 ± 2.5 vs 56.3 ± 3.6 vs 128.2 ± 12.4 mL/min/kg; p < 0.01), and the elimination half-life prolonged(912.8 ± 98.0 vs 825.8 ± 141.7 vs 229.1 ± 76.4 min; p < 0.01). Other PK parameters were also changed with statistically significants. Data shown above implicate the interactions between PAH and KETO or INDO. And the net secretion clearances(CLS) were deduced and compared to the control, the CLS of PAH decreased(after administrated with KETO: 3.1 ± 1.7 vs 4.4 ± 0.7 vs 9.2 ± 1.6 mL/min/kg; p < 0.05, or INDO: 0.2 ± 0.7 vs 3.0 ± 1.2 vs 9.2 ± 1.6 mL/min/kg; p < 0.05). Meanwhile, the CLS of KETO and INDO decreased(KETO: 43.0 ± 4.3 vs 55.2 ± 17.6 vs 123.5 ± 37.7 mL/min/kg; p < 0.05, and INDO: 10.2 ± 1.5 vs 27.4 ± 5.4 vs 70.1 ± 18.3 mL/min/kg; p < 0.05), respectively, which were statistically significant and implied the interactions on the secretion via OAT1, and altered the PK parameters of PAH, INDO and KETO significantly.

並列關鍵字

Pharmacokinetic,rabbit,transporter,drug-drug interaction

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