| 英文摘要
| Rheumatoid arthritis (RA) is an auto-immune disease with synovitis, joint pain and deformity in pathological features that seriously affects the patientu0027s 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. |
