Naproxen、Ibuprofen、Indomethacin及Leflunomide 在膠原蛋白誘發關節炎大鼠上的藥物動力學性質探討

Abstract

類風濕性關節炎是以關節滑膜慢性發炎為主要病理特徵征的一種自身免疫疾病，該疾病可以引起關節的腫痛以及周邊軟骨的破壞，最終引起關節畸形并出現不同程度殘疾。隨著對於類風濕性關節炎病理機制的了解，已有許多藥物可用於治療這項疾病。根據作用方式，目前治療藥物大致可以分為幾類：非類固醇抗發炎藥物，糖皮質激素類，疾病修飾抗風濕藥物（慢作用抗風濕藥物），細胞因子抑制劑與T細胞作用生物製劑。其中，非類固醇抗發炎藥物和改變病情藥物是目前最常用於類風溼性關節炎症的藥物。 本論文旨在研究評估非類固醇抗發炎藥物naproxen、ibuprofen、indomethacin和改變病情藥物leflunomide在膠原蛋白誘發關節炎疾病的大鼠之藥動學特性。研究結果顯示類風濕性關節炎大鼠相較健康大鼠血中cytokine濃度interleukin-1β, interleukin-6, TNF-α都有增加的趨勢，並且TNF-α增加到2.8倍。並且ATS和ATL兩個衡量肝臟毒性的指標在day17給藥24小時後，均上升了1.6倍。 連續6天投予leflunomide後，在Day23觀察到大鼠肝臟病理形態發生明顯改變。在藥動學性質部分，實驗結果顯示，相較於健康鼠試驗藥物 (naproxen、ibuprofen、indomethacin和leflunomide)在關節炎模型大鼠之血中濃度皆有明顯改變。其中，leflunomide四小時內的AUC變成2.1倍，Cmax變為2.05倍，Cl清除率下降到原來37.5%。除此之外，Indomethacin, naproxen及ibuprofen的24小時AUC均有上升的趨勢，其中ibuprofen的AUC上升到1.17倍，indomethacin的清除率下降到原來一半。 以上結果顯示關節炎可顯著影響naproxen、ibuprofen、indomethacin和leflunomide之藥動學性質。其所造成這些藥物藥動學性質的改變或許與CIA大鼠全身發炎所導致代謝活性改變有關。

Rheumatoid arthritis (RA) is an auto-immune disease with synovitis, joint pain and deformity in pathological features that seriously affects the patient's daily life. In the past few decades, along with the elucidation of pathogenesis, a number of anti-rheumatoid arthritis drugs have been developed and available on the market. According to the action of mechanisms, these drugs can be classified to several categories: the nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, disease modifying anti-rheumatic drugs (DMARDs), and biological agents that specifically inhibit interleukin-1β, interleukin-6, and TNF-α or directly target on T lymphocytes. Among these, the NSAIDs and DMARDs are widely used in the treatment of RA. The objective of this thesis is to investigate the effects of RA on the pharmacokinetics of NSAIDs (naproxen、ibuprofen、indomethacin) and DMARDs (leflunomide) in animals with and without collagen-induced arthritis (CIA). The results show that the plasma levels of interleukin-1β, interleukin-6 and TNF-α are likely to increase in CIA rats, example that the concentraction of TNF-α increase by 2.8-fold compare to controls. The ALT (Alanine Aminotransferase), AST (Aspartate Aminotransferase) value referring for the liver toxicity increased by 1.6-fold at 24 hours after the dosing of leflunomide on day-17. Following 6-day consecutive administrations of leflunomide, the liver morphology was also changed on day-23. In terms of pharmacokinetic properties, following oral administratins, the plasma concentration profiles of naproxen, ibuprofen, indomethacin, and leflunomide were all changed in CIA rats, compared to the controls. The AUC and Cmax values of leflunomide increased by 2.1-fold and 2.05-fold, respectively, whereas clearance decreased by 2.67-fold first 4 hours after dosing. While the AUC of ibuprofen increased by 1.17-fold, and also a growing trend comes to indomethacin, naproxen. Taken together, these data demonstrate that RA has significant impacts on the pharmacokinetics of naproxen, ibuprofen, indomethacin, and leflunomide. The changes in pharmacokientics of these drugs may be attributed to different metabolic activities caused by systemic inflammatory responses in CIA rats.