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目的:建立简便、快速、可靠的测定人血浆中S-奥拉西坦和R-奥拉西坦2种异构体浓度的HPLC测定方法,并用于2种异构体在人体内的药代动力学对比研究。方法:采用大赛璐CHIRALPAK ID(4.6 mm×250 mm,5μm)色谱柱,以异丙醇-无水乙醇-三氟乙酸(82∶18∶0.1)为流动相,流速1.2 m L·min-1,紫外检测波长为210 nm,柱温35℃,内标物为吡拉西坦。12名中国健康志愿者(男女各半)根据体重随机分组,采用双周期、双交叉给药设计。结果:2种异构体血浆药物浓度测定无内源性干扰,最低定量限为5.000 mg·L~(-1)。S-奥拉西坦与R-奥拉西坦质量浓度在5.000～400.0 mg·L~(-1)范围内线性关系均良好,相关系数分别为0.998 2和0.998 7。日内、日间精密度的RSD分别为1.6%～7.9%和2.3%～8.9%。准确度分别在94.0%～103.1%和91.0%～103.2%范围内。药动学结果显示,健康志愿者静脉滴注3.0 g S-奥拉西坦后S-奥拉西坦在人体内平均Cmax为(172.9±31.09)mg·L~(-1),平均t1/2为(2.22±0.42)h,平均AUC0-∞为(364.0±55.45)mg·L~(-1)·h;健康志愿者静脉滴注6.0 g消旋奥拉西坦后S-奥拉西坦与R-奥拉西坦在人体内平均Cmax分别为(183.8±37.13)mg·L~(-1)和(180.3±37.65)mg·L~(-1),平均t_(1/2)分别为(2.24±0.44)h和(2.34±0.47)h,平均AUC_(0-∞)分别为(386.7±70.61)mg·L~(-1)·h和(389.3±74.41)mg·L~(-1)·h。结论:经方法学验证,所建立的HPLC手性固定相法可应用于奥拉西坦两异构体在中国健康志愿者体内的药代动力学对比研究。
OBJECTIVE: To establish a simple, rapid and reliable method for the determination of 2 isomers of S-oxiracetam and R-oxiracetam in human plasma by HPLC and to study the pharmacokinetics of 2 isomers in human Kinetic contrast study. Methods: The mobile phase consisted of Daicel CHIRALPAK ID (4.6 mm × 250 mm, 5 μm) column with isopropanol - absolute ethanol - trifluoroacetic acid (82:18:0.1) as mobile phase at a flow rate of 1.2 mL · min -1 , UV detection wavelength of 210 nm, column temperature 35 ℃, internal standard substance is piracetam. Twelve Chinese healthy volunteers (half male and half female) were randomly divided into groups according to body weight, and were designed in a double-cycle, double-crossover design. Results: There was no endogenous interference in the determination of plasma concentration of the two isomers. The lowest limit of quantification was 5.000 mg · L -1. The linear relationship between S-oxiracetam and R-oxiracetam in the range of 5.000-400.0 mg · L -1 was good with the correlation coefficients of 0.998 2 and 0.998 7, respectively. The intra-day and inter-day precision RSD were 1.6% ~ 7.9% and 2.3% ~ 8.9%, respectively. Accuracy were 94.0% ~ 103.1% and 91.0% ~ 103.2% range. Pharmacokinetics results show that healthy volunteers after intravenous infusion of 3.0 g S-oxiracetam S-oxiracetam in the human average Cmax was (172.9 ± 31.09) mg · L -1, the average t1 / 2 was (2.22 ± 0.42) h, the mean AUC0-∞ was (364.0 ± 55.45) mg · L -1 · h. After healthy volunteers received intravenous infusion of 6.0 g racemic oxiracetam, The average Cmax of Tan and R-Oxiracetam were (183.8 ± 37.13) mg · L -1 and (180.3 ± 37.65) mg · L -1, respectively, with an average of t 1/2 (2.24 ± 0.44) h and (2.34 ± 0.47) h respectively, and the average AUC 0 -∞ were 386.7 ± 70.61 mg · L -1 · h and 389.3 ± 74.41 mg · L -1, respectively (-1) · h. Conclusion: The established method of HPLC chiral stationary phase method can be applied to the comparative study of the pharmacokinetics of two isomers of oxiracetam in Chinese healthy volunteers.