LC-MS/MS法测定右溴苯那敏的血药浓度及其药动学特征评价(英文)

Dexbrompheniramine determination and pharmacokinetics in human plasma using LC-MS/MS

目的建立液相色谱-串联质谱(LC-MS/MS)法测定人血浆中右溴苯那敏的浓度,并评价右溴苯那敏在健康受试者体内的药动学特征。方法血浆经参有氯苯那敏为内标的甲醇沉淀后在Inertsil ODS-3柱(150 mm×2.1 mm,5μm)上分离,流动相采用含10 mmol·L^(-1)甲酸铵的甲醇/水/甲酸(60∶40∶0.1,V/V/V)溶液。串联质谱Sciex API 3000采用正电喷雾离子源和多反应监测的扫描模式。结果右溴苯那敏在0.1～40μg·L^(-1)内线性良好,定量下限为0.1μg·L^(-1)。方法的准确度为87%～113%,批内、批间的RSD均<15%。右溴苯那敏的主要药动学参数ρ_(max)、t_(max)、t_(1/2)、AUC_(0→t)和AUC_(0→∞)在单剂量给药后分别为:(3.58±1.14)μg·L^(-1)、(9.42±2.94)h、(18.46±9.48)h、(108.4±53.97)μg·h·L^(-1)和(126.3±73.91)μg·h·L^(-1);在多剂量给药后分别为:(14.59±6.75)μg·L^(-1),(6.35±2.09)h、(21.40±7.74)h、(487.9±316.2)μg·h·L^(-1)和(578.0±437.3)μg·h·L^(-1)。稳态时的药动学参数AUC^(ss)、ρ_(min)、ρ_(av)和DF分别为:(153.0±74.47)μg·h·L^(-1)、(12.07±5.84)μg·L^(-1)、(12.75±6.21)μg·L^(-1)和(21.2±7.7)%。结论本方法专属性强,精确,灵敏度高,操作简单,快速。结果表明单剂量和多剂量给药后ρ_(max)、t_(max)和AUC_(0→t)之间的差异有统计学意义,右溴苯那敏在体内有蓄积。

AIM To develop a LC-MS/MS method for determining dexbrompheniramine （DBP） in hmnan plasma and evaluate the pharmacokinetics of DBP in Chinese healthy subjects after a single and multiple oral doses. METHODS Plasma samples were pretreated by methanol spiked with chlompheniramine as internal standard, then separated by chromatography on an Inertsil ODS-3 column （ 150 mm × 2.1 mm, 5 μm） using a mobile phase consisted of methanol- water-formic acid （60：40：0.1, V/V/V） containing 10 mmol· L^-1 ammonium formate. Detection was carried out on a Sciex API 3000 using positive electrospray ion source and multiple reaction monitoring scan mode. RESULTS The linear calibration curve was in a range of 0.1 - 40μg· L^- 1 with a limit of quantitation of 0.1μg· L^- 1. The accuracy was within 87 % - 113 % and the relative standard deviation （RSD） of inter-batch and intra-batch precision was less than 15%. The main phannacokinetic parameters ρmax, tmax, t1/2, AUC0-1 and AUC0-∞ were （3.58± 1.14）pg·L^-1, （9.42 ± 2.94）h, （18.46 ± 9.48）h, （108.4 ± 53.97） pg·h·L^-1 and （126.3 ± 73.91） pg·h·L^-1 after a single dose and （14.59 ± 6.75）pg·h·L^-1, （6.35 ± 2.09）h, （21.40± 7.74）h, （487.9 ±316.2）pg·h·L^-1 and （578.0 ±437.3）pg·h·L^-1 after multiple doses, respectively. The steady-state pharmacokinetic parameters AUC^88, Pain, Pay and DF were （153.0 ± 74.47）μg·L^-1, （12.07 ＋ 5.84）μg·L^-1, （12.75 ± 6.21）μg·L^-1 and （21.2± 7.7）%, respectively. CONCLUSION The method is specific, simple, rapid, precise, accurate and sensitive. Statistical analysis shows sig- nificant differences in ρmax, tmax and AUC0-1 between single and multiple doses administration. There is accumulation of DBP after multiple doses.