阿姆西汀在模拟失重大鼠体内检测方法建立及药代动力学研究

Detection method establishment and pharmacokinetics of ammuxetine in rats under microgravity conditions

目的研究常压和失重状态下抗抑郁新药阿姆西汀(ammuxetine)的大鼠药代动力学差异。方法建立高效快速测定大鼠血浆中阿姆西汀药物浓度的超高效液相色谱质谱联用法(UPLC-MS/MS)。建立SD大鼠Morey-Holton尾吊模型,失重组大鼠尾吊10 d,以常压组大鼠为对照,两组分别单次灌胃给予10 mg/kg盐酸阿姆西汀,于0、0.167、0.5、0.75、1、2、3、4、6、8、12和24 h眼眶取血,分离血浆,采用UPLC-MS/MS测定该药在生物样品中的药物浓度,并计算药物的动力学参数。结果在1～500 ng/ml浓度范围内,血浆中阿姆西汀的线性关系良好,日内与日间精密度均<12%,低、中、高3个浓度(2、100和400 ng/ml)提取回收率为96.2%～111.5%,无明显基质效应。相比常压组,模拟失重组药代动力学发生显著变化。其中,药物半衰期、达峰浓度和生物利用度的差异有统计学意义(P<0.05),相对生物利用度为398.2%。结论相比常压下,模拟失重10 d后阿姆西汀药代动力学特性显著改变。

Objective To investigate the pharmacokinetic difference of the new antidepressant drug,ammuxetine(AMXT),under the gravity and microgravity conditions in rats.Methods A highly effective and rapid ultra-performance liquid chromatographytandem mass spectrometry(UPLC-MS/MS)method was established and validated for quantitation of AMXT in rat plasma.MoreyHolton′s rat tail-suspension model was established using SD rats.Rats in the simulated microgravity group were tail-suspended for 10 days.Rats in normal gravity group were used as control.Both groups were given AMXT at a dose of 10 mg/kg(ig).The plasma samples were collected at 0,0.167,0.5,0.75,1,2,3,4,6,8,12 and 24 h after administration,and the UPLC-MS/MS method was used to determine the concentration of AMXT in the plasma samples.Results The UPLC-MS/MS method showed good linearity over the range of 1-500 ng/ml.Intra-and inter-day precisions were both less than 12%.The extraction recoveries of AMXT at the three concentrations(2,100 and 400 ng/ml)ranged from 96.2%to 111.5%.Compared with the normal gravity group,the pharmacokinetic characteristics of AMXT significantly differed in the simulated microgravity group.Among them,the differences in the half-life(t1/2),maximum concentration(Cmax)and area under the curve(AUC)had statistical significance(P<0.05),and the relative bioavailability was 398.2%.Conclusion Compared with the normal gravity conditions,the pharmacokinetic characteristics of AMXT in rats have been significantly changed under the simulated microgravity conditions.