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目的建立快速、灵敏、高效的柱前衍生化液相色谱-串联质谱法测定人血浆中的硫普罗宁含量。方法血浆样品经丙烯酸甲酯衍生化后,以乙醚-二氯甲烷(3∶2,V/V)进行液-液萃取,色谱分离采用Kromasil C18柱,流动相为甲醇-水-甲酸(80∶20∶0.1,V/V/V),质谱检测采用选择反应监测(SRM)模式,在电喷雾负离子化方式下,分别监测离子反应m/z 248→m/z 74(硫普罗宁衍生物)和m/z 248→m/z 119(内标N-乙酰基-L-半胱氨酸衍生物)。测定了18名健康受试者口服硫普罗宁肠溶片300 mg后不同时刻血浆中硫普罗宁的浓度,采用DAS 2.0软件以非房室模型计算药动学参数。结果血浆中硫普罗宁的线性范围为0.05～5.0 mg.L-1;日内和日间精密度均小于12.7%,准确度在92.1%～100.8%之间,提取回收率大于64.4%。硫普罗宁的主要药动学参数:t1/2为(8±s 3)h,tmax为(4.1±0.8)h,ρmax为(3.9±0.8)mg.L-1,AUC0～t为(14±4)mg.h.L-1,AUC0～∞为(17±4)mg.h.L-1。结论本方法专属性好、灵敏度高,适合于硫普罗宁的人体药动学研究。
Objective To establish a rapid, sensitive and efficient pre-column derivatization liquid chromatography-tandem mass spectrometry for the determination of tiopronin in human plasma. Methods The plasma samples were derivatized with methyl acrylate and subjected to liquid-liquid extraction with diethyl ether-methylene chloride (3: 2, V / V). The chromatographic separation was performed on a Kromasil C18 column using methanol- water- 20: 0.1, V / V / V). The mass spectra were monitored by selective reaction monitoring (SRM) mode. The electrospray negative ionization mode was used to monitor the ion reaction m / z 248 → m / And m / z 248 → m / z 119 (internal standard N-acetyl-L-cysteine derivative). The plasma concentration of tiopronin was measured in 18 healthy volunteers after oral administration of 300 mg of tiopronin at different time points. Pharmacokinetic parameters were calculated by DAS 2.0 software in a non-compartmental model. Results The linear range of tiopronin in plasma was 0.05-5.0 mg · L -1. The intra-day and inter-day precision was less than 12.7% with the accuracy of 92.1% -100.8%. The extraction recovery was more than 64.4%. The main pharmacokinetic parameters of tiopronin: t1 / 2 was (8 ± s3) h, tmax was (4.1 ± 0.8) h, ρmax was (3.9 ± 0.8) mg.L-1, and AUC0 ~ t was ± 4) mg.hL-1 and AUC0 ~ ∞ (17 ± 4) mg.hL-1. Conclusion This method is specific and sensitive and suitable for the study of human body pharmacokinetics of tiopronin.