Fluvastatin、atorvastatin及pravastatin於膠原蛋白誘發之關節炎大鼠上藥物動力學性質之探討

Abstract

本研究的目的為探討在膠原蛋白誘發之關節炎 (CIA) 的疾病狀態下，對fluvastatin、atorvastatin與pravastatin於大鼠上的藥物動力學性質之影響。結果顯示，CIA大鼠口服fluvastatin與atorvastatin後，血中濃度與全身性的藥物暴露量均顯著高於control大鼠，而直接經由肝門靜脈給予fluvastatin與atorvastatin後也可以得到相似之結果。然而當pravastatin口服用於CIA大鼠後，其血中濃度與全身性的藥物暴露量與control大鼠相較下均沒有明顯的差異。而經由pravastatin直接經由肝門靜脈給藥後，亦無太大的差異性產生。從藥物動力學分析中推測fluvastatin與atorvastatin在CIA大鼠的血中濃度上升是因其擬似清除率下降所致。進一步發現fluvastatin與atorvastatin在CIA大鼠之肝細胞吸收清除率均有顯著下降，其中fluvastatin更在CIA大鼠之肝臟microsome代謝有受到抑制的現象。在肝臟及肌肉毒性方面，雖然fluvastatin與atorvastatin在CIA大鼠上有明顯的血中濃度增加，但血漿中肝臟毒性指標天門冬胺酸轉胺酶 (AST)、丙胺酸轉胺酶 (ALT) 與肌肉毒性指標肌酸激酶 (CK) 相較於control大鼠並無太大差異。而pravastatin的部分，由於在CIA大鼠與control大鼠上沒有明顯的血中濃度差異，因此在肝臟及肌肉毒性反應上亦沒有看到明顯的差異存在。

The objective of the present study was to investigate the pharmacokinetic properties of fluvastatin, atorvastatin and pravastatin in collagen-induced arthritis (CIA) rats. When fluvastatin and atorvastatin were given orally, the plasma levels and systemic exposures of fluvastatin and atorvastatin were significantly higher in CIA rats than in control rats. Also, the results from portal vein injection were similar to those of oral doing of fluvastatin and atorvastatin. In contrast, there were no differences in the plasma level and systemic exposure of pravastatin between CIA and control rats. The pharmacokinetic analysis suggested that the increased plasma levels of fluvastatin and atorvastatin may be due to the decreased apparent clearances in CIA rats. Furthermore, the hepatic uptake clearances of fluvastatin and atorvastatin were significantly reduced, while the metabolism of fluvastatin was also slightly inhibited by hepatic microsome in CIA rats. However, the higher plasma levels of fluvastatin and atorvastatin in CIA rats did not cause a significant increase in the levels of AST (aspartate aminotransferase), ALT (alanine aminotransferase), and CK (creatine kinase), compared with control rats. In the part of pravastatin, there were also no differences in hepatotoxicity (as measured for AST and ALT) and myotoxicity (as measured for CK) because of the similar plasma levels in CIA and control rats.