類風濕性關節炎對於脂溶性他汀類藥物在大鼠上藥動學影響之探討：從基礎研究到以生理學為基礎之藥動學模式

Abstract

他汀類藥物是常用於類風溼性關節炎之心血管合併症的降血脂藥物。我們先前的研究結果顯示脂溶性他汀類藥物fluvastatin、atorvastatin及simvastatin在以膠原蛋白誘發關節炎大鼠的血中濃度顯著高於對照組。本研究進一步評估類風濕性關節炎對肝臟代謝活性之影響，並分別藉由靜脈注射及以生理學為基礎之藥動學模式(PBPK modeling)來探討關節炎對於這些他汀類藥物藥動學的影響。由我們的結果得知，關節炎大鼠肝臟微粒體的Cyp2c及Cyp3a酵素的最大反應速率明顯低於對照組。在給予靜脈速注後， simvastatin在關節炎大鼠的全身藥物暴露量為對照組的三倍。相反地， fluvastatin或atorvastatin的血中濃度在關節炎大鼠及其對照組間無差異。在關節炎大鼠上，simvastatin的微粒體代謝清除率顯著下降，然而肝細胞攝取清除率卻沒有改變。先前體外試驗之結果被納入PBPK模式中並成功預測fluvastatin及atorvastatin在關節炎大鼠及其對照組的血中濃度時間曲線。這些結果顯示類風溼性關節炎對於脂溶性他汀類藥物有不同的影響。

Statins are lipid-lowering agents widely used in rheumatoid arthritis (RA) patients with concurrent cardiovascular diseases. Previously, we have demonstrated that the blood concentrations of orally administered lipophilic statins (i.e. fluvastatin, atorvastatin, and simvastatin) were significantly changed in rats with collagen-induced arthritis (CIA). In the present study, we further investigated the impact of RA on the pharmacokinetics of these statins. Accordingly, the effect of RA on metabolic activities of hepatic microsomes was evaluated. Also, the pharmacokinetics of lipophilic statins were examined following intravenous administrations and by physiologically based pharmacokinetics (PBPK) modeling approach. The results showed that maximal metabolic activities (Vm) of Cyp2c and Cyp3a were reduced in liver microsomes of CIA rats, compared with control rats. After single intravenous bolus, the systemic exposure of simvastatin increased by 3-fold in CIA rats, compared with the controls; in contrast, there were no differences in the plasma levels of fluvastatin and atorvastatin between CIA rats and control rats. The microsomal metabolic clearance of simvastatin but not hepatic uptake clearance was significantly decreased in CIA rats. Results from previous in vitro experiments were incorporated into the established PBPK model and the concentration-time profiles of fluvastatin and atorvastatin were successfully reproduced in either control rats or the CIA rats. These findings show the differential influence of RA in the pharmacokinetics of lipophilic statins.