葡萄糖基化丙泊酚溶液型注射剂在大鼠体内的药物动力学

Pharmacokinetics for the solutable type injections of propofol glycoside in rats

目的:考察葡萄糖基化丙泊酚溶液型注射剂在大鼠体内的药物动力学。方法:建立液相色谱-高分辨质谱联用方法,用以测定大鼠体内丙泊酚血药浓度;通过对大鼠尾静脉给药,分别给予丙泊酚脂肪乳剂型注射剂和两种葡萄糖基化丙泊酚溶液型注射剂,测定丙泊酚血药浓度,获得药物-时间曲线,并计算药物动力学参数。结果:用C18色谱柱,以水∶甲醇(20∶80,V/V)为流动相,用四极杆-轨道阱高分辨质谱仪进行检测,使用大气压化学电离源,负离子检测,扫描方式采用选择离子监测方式,m/z=177.127 4(丙泊酚),m/z=149.096 1(麝香草酚,内标参照物)。测定方法在50μg/L^10.0 mg/L范围内线性关系良好,最低定量浓度为50μg/L,平均回收率在93.6%~101.1%之间,日内、日间精密度均小于14%。药物动力学结果显示,两种葡萄糖基化丙泊酚溶液型注射剂药物动力学行为一致;同丙泊酚脂肪乳剂型注射剂相比,两种葡萄糖基化丙泊酚溶液型注射剂清除率均明显加快,表观分布容积也相应增大,血液循环中血药浓度-时间曲线下面积减小,消除半衰期与丙泊酚脂肪乳剂型注射剂一致(t1/2约1.5 h)。结论:建立的液相色谱-高分辨质谱联用方法可以用于大鼠体内丙泊酚含量的测定;与丙泊酚脂肪乳剂型注射剂相比,葡萄糖基化丙泊酚溶液型注射剂具有在血液循环中清除率加快、表观分布容积大的特点。

Objective： To estimate the pharmacokinetics for two solution types of propofol glycoside injections in rats. Methods： A high performance liquid chromatography-high resolution mass spectrometry（ HPLC-MS） was established for measuring propofol in rat plasma. Two kinds of propofol glycoside injections were developed and intravenously administered to rats via tail vein,respectively,and a commercially available propofol emulsion injection was intravenously administered as a control. Propofol plasma concentration-time curves were determined,and the pharmacokinetic parameters were estimated. Results： HPLC-MS measurement was performed by using a quadrupole-orbit trap high-resolution mass spectrometer on a C18 chromatographic column. The mobile phase consisted of water and methanol（ 20 ∶ 80,V / V）. The ion source was an atmospheric pressure chemical ion source,and the negative ion was used for detection with a scanning mode of selective ion monitoring in which m / z 177. 127 4 was used for propofol and m / z 149. 096 1 used for thymol as an internal standard. A linear correlation between concentration and peak area ratio was constructed in the range of 50 μg / L- 10. 0 mg / L propofol. The limit of quantification was 50 μg / L propofol. The average recoveries of propofol from plasma were in the range of 93. 6%- 101. 1%,and intra-day or inter-day relative standard deviation for measurement was 14%. The pharmacokinetic results showed that the two kinds of propofol glycoside injections exhibited the same pharmacokinetic behavior. However,the clearance and area under curve values of propofol for the two propofol glycoside injections were evidently increased as compared with those for propofol emulsion injection,respectively. Furthermore,their apparent distribution volumes were increased as well. Nevertheless,the propofol elimination half-life（ t1 /2） value of the newly developed propofol glycoside injections was the same as that of commercial propofol emulsion injection（ approximately 1. 5 h）. Conclusion： The established HPLC-MS method can be used for measuring propofol concentration accurately in rat plasma.The clearance and distribution volumes of propofol glycoside injection are bigger than those of the propofol emulsion injection.