Uraki Misato, Kawase Atsushi, Sayama Hiroyuki, Matsushima Yuka, Iwaki Masahiro
Department of Pharmacy, Faculty of Pharmacy, Kindai University, Higashi-osaka, Osaka 577-8502, Japan.
Department of Pharmacy, Faculty of Pharmacy, Kindai University, Higashi-osaka, Osaka 577-8502, Japan.
J Pharm Sci. 2017 Apr;106(4):1175-1182. doi: 10.1016/j.xphs.2016.12.021. Epub 2017 Jan 3.
The reactive metabolites of diclofenac (DF) such as 1-O-acyl glucuronide (DF-Glu) are hypothesized to result in idiosyncratic hepatotoxicity. However, it is unclear whether inflammation affects the hepatic disposition of DF and its metabolites. To clarify the alterations in the disposition of DF and its metabolites in inflammatory conditions, we performed in situ perfused rat liver experiments. Using adjuvant arthritis rats as a model of inflammation, the elimination of DF, 4'-hydroxydiclofenac, and DF-Glu from the perfusate was observed to be delayed in comparison with the control. Parameter sensitivity analysis for hepatic DF disposition revealed that the area under the plasma concentration-time curve (AUC) and the maximum concentration (C) of DF-Glu in the liver markedly increased along with a decrease in intrinsic excretion clearance of DF-Glu (CL) and an increase in intrinsic glucuronidation clearance (CL) of DF-Glu. It is possible that the elimination of DF-Glu from the perfusate in adjuvant arthritis rats was delayed via reduction of biliary excretion of DF-Glu.
双氯芬酸（DF）的反应性代谢产物，如1-O-酰基葡萄糖醛酸（DF-Glu），被认为会导致特异质性肝毒性。然而，尚不清楚炎症是否会影响DF及其代谢产物在肝脏中的处置。为了阐明炎症条件下DF及其代谢产物处置的变化，我们进行了大鼠原位肝脏灌注实验。以佐剂性关节炎大鼠作为炎症模型，观察到与对照组相比，灌注液中DF、4'-羟基双氯芬酸和DF-Glu的消除延迟。肝脏DF处置的参数敏感性分析表明，肝脏中DF-Glu的血浆浓度-时间曲线下面积（AUC）和最大浓度（C）随着DF-Glu的固有排泄清除率（CL）降低和DF-Glu的固有葡萄糖醛酸化清除率（CL）增加而显著增加。佐剂性关节炎大鼠灌注液中DF-Glu的消除可能是通过减少DF-Glu的胆汁排泄而延迟的。
