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目的建立LC-MS/MS法测定人血浆中左旋氨氯地平血药浓度并进行体内手性转化可能性考察。方法以氯氮为内标,采用CHIRAL-AGP柱(150.0mm×4.0mm,5μm)对氨氯地平消旋体进行分离手性对映体,流动相为10mmol/L乙酸铵缓冲液(pH 4.38)-异丙醇(982,V/V);选择固相萃取法提取10例健康男性受试者单次口服苯磺酸左旋氨氯地平片2.5mg后的血浆样品,大气压化学电离源(APCI)结合正离子MRM扫描分析测定人体内S-(-)-氨氯地平浓度,其中氨氯地平和内标离子对分别是m/z 409.0→237.9和m/z 300.0→282.0。结果 S-(-)-/R-(+)-氨氯地平对映体血药浓度在0.103 1～20.62μg/L范围内线性关系良好(r=0.999 8,r=0.999 7),绝对回收率大于70.0%,相对回收率均在85.0%～115.0%范围内,日内和日间RSD均小于15.0%。10例健康男性受试者单剂量口服苯磺酸左旋氨氯地平片2.5mg后体内不同时间点血浆样品均未检测到R-(+)-氨氯地平对映体,S-(-)-氨氯地平在健康男性受试者体内的药代动力学参数t1/2为(42.77±8.08)h,Cmax为(3.06±0.51)μg/L,tmax为(6.3±1.0)h,MRT为(69.25±8.04)h,AUC0-144为(176.20±31.89)h.μg.L-1,AUC0-∞为(197.92±37.54)h.μg.L-1。结论本方法选择性强,灵敏度高,无杂质干扰,精密度好,成功地应用于苯磺酸左旋氨氯地平人体药代动力学分析,并证实S-(-)-氨氯地平对映体在健康男性受试者体内未发现其手性转化。
Objective To establish a LC-MS / MS method for the determination of the plasma concentration of levamlodipine in human plasma and investigate the possibility of its chiral transformation in vivo. Methods Chiral enantiomers of amlodipine racemate were separated on a CHIRAL-AGP column (150.0 mm × 4.0 mm, 5 μm) using chloro-nitrogen as internal standard. The mobile phase consisted of 10 mmol / L ammonium acetate buffer (pH 4.38 ) -isopropanol (982, V / V). Plasma samples from 2.5 healthy subjects with single oral levamisodipine besylate were extracted from 10 healthy male subjects by atmospheric extraction (-) - amlodipine in human body by APCI combined with positive ion MRM scanning analysis. The amlodipine and internal standard ion pair were m / z 409.0 → 237.9 and m / z 300.0 → 282.0, respectively. Results The linear relationship between the enantiomeric concentrations of S - (-) - / R - (+) - amlodipine in the range of 0.103 1 to 20.62 μg / L was good (r = 0.999 8, r = 0.999 7) The relative recoveries were both within the range of 85.0% ~ 115.0%. The daily and intraday RSDs were all less than 15.0%. Enantiomers of R - (+) - amlodipine and S - (-) - enantiomer were not detected in plasma of 10 healthy male subjects after oral administration of 2.5 mg levamlodipine besylate tablets in different time points. The pharmacokinetic parameters of amlodipine were (42.77 ± 8.08) h, (3.06 ± 0.51) μg / L, tmax was (6.3 ± 1.0) h, MRT was 69.25 ± 8.04) h, AUC0-144 was (176.20 ± 31.89) h.μg.L-1, and AUC0-∞ was (197.92 ± 37.54) h.μg.L-1. Conclusion The method is highly selective, sensitive and has no impurity interference and good precision, and has been successfully applied to the human pharmacokinetics analysis of levamlodipine besylate. The enantiomers of S - (-) - amlodipine No chiral transformation was found in healthy male subjects.