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目的:建立LC-MS/MS法测定人血浆中奈必洛尔的浓度,并对健康人群口服盐酸奈必洛尔片后的药代动力学进行研究。方法:血浆样品以普萘洛尔为内标,用乙醚-二氯甲烷(3∶7)进行液液萃取法处理后,采用高效液相色谱分离系统,色谱柱为Phenomenex Luna系列的C_(18)柱(100 mm×2.00 mm,3μm),流动相为甲醇-水-甲酸(70∶30∶0.1);采用质谱检测系统,ESI离子源,正离子模式,多反应监测(MRM)方式监测m/z 406.2→151.1(奈必洛尔)和m/z 260.3→116.2(内标普萘洛尔)。12名受试者单剂量口服盐酸奈必洛尔片5、10、20 mg,多剂量口服盐酸奈必洛尔片5 mg后采集血浆样品,以HPLC-MS/MS测定奈必洛尔浓度,计算药动学参数并进行统计学分析。结果:奈必洛尔质量浓度在0.05~10 ng·m L~(-1)范围内与色谱响应相关性良好,定量下限为0.05 ng·m L~(-1)。批间和批内精密度RSD均小于9%,准确度在96.6%~99.0%。健康中国人单剂量口服盐酸奈必洛尔片5、10和20mg后主要药动学参数为ρmax分别为(1.34±0.53)ng·m L~(-1)(5 mg),(2.92±1.20)ng·m L~(-1)(10 mg),(5.29±2.04)ng·m L~(-1)(20 mg);AUC0-t分别为(7.34±3.30)ng·h·m L~(-1)(5 mg),(17.04±10.78)ng·h·m L~(-1)(10 mg),(37.81±2.38)ng·h·m L~(-1)(20 mg);多剂量口服5 mg的盐酸奈必洛尔片,ρssmax为(1.47±0.63)ng·m L~(-1),AUCss0-t为(9.90±4.60)ng·h·m L~(-1)。结论:本测定方法经方法学验证,适用于人血浆中奈必洛尔的测定并应用于临床动力学的研究。在考察剂量范围内,盐酸奈必洛尔在健康中国人体内的药动学过程具有线性动力学特征,多剂量服用时无明显蓄积现象,在不同性别人群体内药动学过程无显著差异。
OBJECTIVE: To establish a LC-MS / MS method for the determination of nebivolol in human plasma and to study the pharmacokinetics of nebivolol hydrochloride tablets in healthy volunteers. Methods: The plasma samples were treated with propranolol as the internal standard and treated with liquid-liquid extraction with diethyl ether-methylene chloride (3: 7). The HPLC was performed on a Phenomenex Luna series C18 column ) Column (100 mm × 2.00 mm, 3 μm) with methanol-water-formic acid (70:30:0.1) as the mobile phase. The mass spectra of the compounds were determined by mass spectrometry, ESI source, positive ion mode and MRM / z 406.2 → 151.1 (Nebivolol) and m / z 260.3 → 116.2 (Internal standard propranolol). Twelve subjects took single oral dose of 5, 10 and 20 mg of Nebivolol hydrochloride tablets and 5 mg of Nebivolol hydrochloride tablets orally. The plasma samples were collected and the concentration of Nebivolol was determined by HPLC-MS / MS. Pharmacokinetic parameters were calculated and statistically analyzed. Results: The correlation coefficient of nebivolol with the chromatographic response was good in the range of 0.05 ~ 10 ng · m L -1 with the lower limit of quantitation of 0.05 ng · m L -1. The inter-batch and intra-batch precision RSDs were less than 9% and the accuracy was between 96.6% and 99.0%. The pharmacokinetic parameters of 5, 10 and 20 mg naliborol hydrochloride tablets were (1.34 ± 0.53) ng · m L -1 (5 mg), (2.92 ± 1.20 ) (ng · m L -1) (10 mg) and (5.29 ± 2.04) ng · m L -1 (20 mg), respectively. The AUC 0 -t were (7.34 ± 3.30) ng · h · m L (-1) (5 mg), (17.04 ± 10.78) ng · h · m L -1 (10 mg), (37.81 ± 2.38) ng · h · m L -1 (20 mg ). The dosage of 5 mg naliballor hydrochloride orally taken orally was (1.47 ± 0.63) ng · m L -1 and AUCss0-t was (9.90 ± 4.60) ng · h · m L ~ (- 1). Conclusion: This assay is validated by methodology and is suitable for the determination of Nebivolol in human plasma and its application in clinical kinetics. The pharmacokinetics of Nebivolol Hydrochloride in healthy Chinese had a linear kinetic profile during the study dose range, no significant accumulation in multiple doses, and no significant differences in pharmacokinetics among different sex populations.