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目的建立检测人血浆中辛伐他汀的超快速液相色谱-串联质谱法(UFLC-MS/MS),从而考察2种辛伐他汀片的相对生物利用度。方法血浆样品经甲基叔丁基醚液液萃取后,经Shim-pack XR-ODS色谱柱分离,采用梯度洗脱模式,流动相为水(A)-乙腈(B),梯度条件为0.01~3 min,B:80%~90%;3~3.5 min,B:90%~95%,3.51~5 min,B:80%。多反应离子监测(MRM)模式进行定量分析,用于监测的离子反应对分别为m/z 441.2→325.1(辛伐他汀)和m/z 427.2→325.2(内标洛伐他汀)。20名男性健康受试者随机双周期双交叉方式分别口服单剂量辛伐他汀试验制剂及参比制剂40 mg后于不同的时间点采血,并按照所建立的方法进行含量测定,并通过Phoenix WinNonlin 6.0软件评价2种制剂的药动学参数及生物利用度。结果血浆中辛伐他汀在0.1~20 ng·mL-1内线性关系良好(0.995 4),最低检测限为0.1 ng·mL-1,提取回收率63.9%~83.8%,日内精密度<7.1%,日间精密度<10.0%。受试制剂和参比制剂的主要药动学参数分别为:t1/2(3.96±1.65)和(3.77±1.75)h;ρmax(8.364±4.990)和(8.440±4.857)ng·mL-1;t max:(1.71±1.19)和(1.74±1.10)h;AUC0-t(29.74±13.05)和(31.16±13.92)ng·h·mL-1;AUC0-∞(32.35±14.56)和(33.39±14.55)ng·h·mL-1。以AUC0-t计算,受试制剂辛伐他汀的相对生物利用度为(97.3±24.3)%。结论本方法简单,快速,灵敏,成功应用于辛伐他汀生物等效性研究,辛伐他汀受试制剂相对参比制剂生物等效。
OBJECTIVE To establish an ultra-fast liquid chromatography-tandem mass spectrometry (UFLC-MS / MS) method for the determination of simvastatin in human plasma, and to investigate the relative bioavailability of two simvastatin tablets. Methods The plasma samples were separated on a Shim-pack XR-ODS column by liquid-liquid extraction with methyl tert-butyl ether. The gradient elution was performed with a mobile phase of water (A) -acetonitrile (B) 3 min, B: 80% -90%; 3 ~ 3.5 min, B: 90% ~ 95%, 3.51 ~ 5 min, B: 80%. Multiple reaction ion monitoring (MRM) mode was used for quantitative analysis. The ion reaction pairs for monitoring were m / z 441.2 → 325.1 (simvastatin) and m / z 427.2 → 325.2 (internal standard lovastatin), respectively. Twenty male healthy subjects were randomized to double-cycle and double-crossover methods to take single-dose simvastatin test preparations and reference preparations 40 mg respectively. Blood samples were taken at different time points and determined according to the established method. 6.0 software to evaluate the pharmacokinetic parameters and bioavailability of two kinds of preparations. Results The linearity of simvastatin in plasma was good (0.995 4) in 0.1-20 ng · mL-1, the detection limit was 0.1 ng · mL-1, the recovery was 63.9% -83.8%, the intra-day precision was less than 7.1% , Daytime precision <10.0%. The main pharmacokinetic parameters of the tested and reference preparations were: t1 / 2 (3.96 ± 1.65) and (3.77 ± 1.75) h; ρmax (8.364 ± 4.990) and (8.440 ± 4.857) ng · mL- AUC0-t (29.74 ± 13.05) and (31.16 ± 13.92) ng · h · mL-1; AUC0-∞ (32.35 ± 14.56) and (33.39 ± 14.55) ng · h · mL-1. The relative bioavailability of simvastatin in the test formulation was (97.3 ± 24.3)% based on AUC0-t. Conclusion The method is simple, rapid and sensitive and has been successfully used in the bioequivalence study of simvastatin and the bioequivalence of simvastatin in comparison with the reference formulation.