Ogiso T, Iwaki M, Kinoshita T, Tanino T, Paku T
Faculty of Pharmaceutical Sciences, Kinki University, Osaka, Japan.
J Pharm Sci. 1994 Jan;83(1):34-7. doi: 10.1002/jps.2600830109.
A prodrug of indomethacin, indomethacin octyl ester (IM-OE), was synthesized and its pharmacokinetics was investigated in rat. To describe the time course of the plasma indomethacin and IM-OE after intravenous (iv) and oral administrations, a pharmacokinetic model with four compartments was developed. Indomethacin rapidly appeared in plasma after iv administration of IM-OE and declined in a monoexponential manner, with a rapid decline and low plasma levels of IM-OE. The plasma concentrations of indomethacin after oral administration of IM-OE were much lower than those after oral administration of indomethacin. The high concentrations of IM-OE compared with indomethacin were detected in liver 3 h after oral dosing of the prodrug, although IM-OE was not detected in plasma. A good fit was obtained between the observed and calculated curves based on the model, which includes a conversion rate constant of IM-OE to indomethacin for both iv and oral dosings of IM-OE. Additionally, the model could successfully describe the plasma concentration versus time profiles after indomethacin dosings.
合成了吲哚美辛的前药吲哚美辛辛酯（IM-OE），并在大鼠体内研究了其药代动力学。为了描述静脉注射（iv）和口服后血浆中吲哚美辛和IM-OE的时间进程，建立了一个具有四个房室的药代动力学模型。静脉注射IM-OE后，吲哚美辛迅速出现在血浆中，并呈单指数下降，IM-OE下降迅速且血浆水平较低。口服IM-OE后血浆中吲哚美辛的浓度远低于口服吲哚美辛后的浓度。在前药口服给药3小时后，肝脏中检测到与吲哚美辛相比高浓度的IM-OE，尽管血浆中未检测到IM-OE。基于该模型，观察曲线和计算曲线之间获得了良好的拟合，该模型包括IM-OE静脉注射和口服给药时转化为吲哚美辛的转化率常数。此外，该模型可以成功描述吲哚美辛给药后血浆浓度随时间的变化曲线。
