不同制备工艺伏立康唑注射剂在大鼠体内的代谢情况

Metabolism of voriconazole injection with different preparation processes in rats

目的分析不同制备工艺伏立康唑注射剂在大鼠体内的代谢情况。方法16只雄性Sprague-Dawley大鼠按照随机数字表法分为2组,经大鼠尾静脉注射国产(四川美大康华康药业有限公司生产)与进口(美国辉瑞制药有限公司生产)伏立康唑注射剂,剂量40 mg/kg,采用高效液相色谱-串联质谱(HPLC-MS/MS)法测定5、30、60、120、240、360、480、720、1440 min不同制备工艺伏立康唑注射剂血药浓度,采用DAS2.0药动学软件分析伏立康唑注射剂血药浓度-时间数据,并对比不同制备工艺伏立康唑注射剂血浆药物动力学参数的差异。结果国产与进口伏立康唑注射剂在大鼠体内主要药代动力学参数到达最大血药浓度的时间(Tmax)、最大血药浓度(Cmax)、清除率(CL)、24 h药物浓度-时间曲线下面积(AUC 0~24 h)以及平均滞留时间(MRT)比较[(5.00±0.10)min、(28.4±2.4)μg/ml、(3.5±1.6)ml·h^(-1)·kg^(-1)、(249±27)μg·h^(-1)·ml^(-1)、(7.7±1.3)h和(5.00±0.20)min、(30.1±2.3)μg/ml、(2.4±0.6)ml·h^(-1)·kg^(-1)、(233±20)μg·h^(-1)·ml^(-1)、(6.8±1.0)h],差异均无统计学意义(P>0.05);大部分组织在给药后480 min逐渐降低,各主要脏器以及组织药物浓度与血浆药物消除具有一致性。结论不同制备工艺伏立康唑注射剂在大鼠体内的药代动力学参数接近,在不同脏器组织内的暴露也无明显差异,药代动力学过程无明显差异。

Objective To analyze the metabolism status of voriconazole injection with different prepara-tion processes in rats.Methods A total of 16 male Sprague-Dawley rats were divided into two groups according to the random number table method.One group received the domestically-produced voriconazole injection(Sichuan Meidakang Huakang Pharmaceutical Co.,Ltd.),while another group received the imported voriconazole injection(Pfizer Pharmaceuticals Ltd.),both through tail vein injection,at a dose of 40 mg/kg.High-performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS)was used to determine the blood concentration of voriconazole injection at 5,30,60,120,240,360,480,720 and 1440 min in different preparation processes.DAS2.0 pharmacokinetic software was adopted to analyze the blood concentration-time data of voriconazole injec-tion,and the differences in plasma pharmacokinetic parameters of voriconazole injection with different preparation processes.Results There were no statistically significant differences in the time of main pharmacokinetic param-eters reaching the maximum plasma concentration(Tmax),maximum plasma concentration(Cmax),clearance rate(CL),the area under the 24 h drug concentration-time curve(AUC 0~24 h)and mean retention time(MRT)of do-mestic and imported voriconazole injections[(5.00±0.10)min vs(5.00±0.20)min,(28.4±2.4)μg/ml vs(30.1±2.3)μg/ml,(3.5±1.6)ml·h^(-1)·kg^(-1)vs(2.4±0.6)ml·h^(-1)·kg^(-1),(249±27)μg·h^(-1)·ml^(-1)vs(233±20)μg·h^(-1)·ml^(-1),(7.7±1.3)h vs(6.8±1.0)h](P>0.05).Most tissues gradually decreased at 480 min after administration,and the main organs and tissue drug concentrations were consistent with plasma drug elimination.Conclusion The pharmacokinetic pa-rameters of voriconazole injection with different preparation processes are similar in rats,and there is no signifi-cant difference in exposure in different organs and tissues.Different preparation processes do not substantially change the pharmacokinetics of voriconazole.