新型钾通道开放剂（QO-58）在大鼠体内药代动力学研究

摘要

目的：建立一种新型高效M型钾通道开放剂(QO-58)体内检测方法,研究其在大鼠体内的药代动力学特征。方法大鼠灌胃( ig,25、50、100 mg·kg-1)3个剂量和静脉单剂量注射15 mg·kg-1 QO-58,于给药后不同时间采集血样,乙腈沉淀蛋白,HPLC内标法测定血药浓度,DAS2.1.1软件计算药代动力学参数。结果血浆标准曲线在0．1~160 mg· L-1范围内线性良好。血浆中QO-58的最低定量限( LQD )为0．1 mg·L-1。方法回收率为89．56%~101．38%,精密度良好,日内和日间RSD中、高浓度样品均小于15%,低浓度样品小于20%。大鼠灌胃及注射给药,药时曲线均呈二室模型。 QO-58灌胃给药25、50、100 mg · kg-1的主要药动学参数如下：Cmax ( mg·L-1)为8．25、16．29、18．27；T 12β( h)：8．24、5．01、5．92；AUC0-∞( g · min · L-1)：261．94、189．57、90．65。结论所建立的HPLC方法简单、专属性强,适用于QO-58在大鼠体内的药代动力学研究。%Aim To develop a sensitive, specific and accurate method for the pharmacokinetic study of QO-58 ( a novel M channel opener ) in rats after intragas-tric ( ig) and intravenous ( iv) administration. Meth-ods QO-58 was administered at the doses of 25,50, 100 mg · kg-1 ( ig ) and at single dose of 100 mg · kg-1(iv), respectively. Blood samples were obtained at intervals after each administration. Plasma samples were deproteinized with acetonitrile after addition of in-ternal standard, and detected by RP-HPLC. The main parameters of pharmacokinetics were calculated by DAS2. 1. 1 software. Results The calibration curve in plasma was linear over the range of 0. 1 ~160 mg · L-1 in rat plasma, and the limit of detection ( LOD) was 0. 1 mg · L-1 . The intra-day and inter-day RSD was less than 20%. The recovery of QO-58 in rat plas-ma was 89. 56% ~101. 38%. The concentration-time curves of QO-58 in rat palsma were consistent with the two-compartment model after both oral and intravenous administration. The main pharmacokinetic parameters for QO-58 following oral administration with three doses (25, 50, 100 mg· kg-1 ) in rat were as follows:Cmax (mg·L-1):8.25,16.29,18.27;T12β(h): 8.24, 5. 01, 5. 92; AUC0-∞ ( g · min · L-1 ):261. 94, 189. 57,90. 65. Conclusion The developed method is simple and specific, and is suitable for preclinical pharmacokinetic studies of QO-58 .