目的 建立LC-MS/MS测定人血浆中缬沙坦浓度,应用于缬沙坦片空腹和餐后药动学研究。方法 采用Waters Symmetry C18(3.9 mm×150 mm, 5 μm)色谱柱,流动相为甲醇-10 mmol·L-1醋酸铵水溶液(含0.05%甲酸)=70∶30 (V/V)。12名受试者随机分为2组,每组6名,1组进行缬沙坦片(80 mg)单次空腹给药人体药动学研究,另1组进行单次餐后给药人体药动学研究。通过LC-MS/MS测定缬沙坦浓度。结果 缬沙坦血浆在10.00~5 000 ng·mL-1内线性良好。6名受试者空腹状态下,口服缬沙坦片后,血浆中缬沙坦的ρmax为(3 156±869)ng·mL-1,AUC0-24 h为(20 181±3 535)ng·h·mL-1,AUC0-∞为(20 576±3 540)ng·h·mL-1,t1/2为(6.72±1.25)h,tmax为(3.67±0.98)h。6名受试者餐后状态下,口服缬沙坦片后,血浆中缬沙坦的ρmax为(2 502±508)ng·mL-1,AUC0-24 h为(14 654±3 715)ng·h·mL-1,AUC0-∞为(14 816±3 681)ng·h·mL-1,t1/2为(5.84±2.14)h,tmax为(3.75±1.48)h。结论 该方法简便、特异性高、灵敏度高,可用于受试者空腹和餐后口服80 mg缬沙坦片后血浆样品中缬沙坦药动学研究。高脂高热量饮食对缬沙坦片的药动学特征有影响,餐后口服缬沙坦片ρmax降低约20.72%,AUC降低约27.39%,tmax无显著变化。
Abstract
OBJECTIVE To establish an LC-MS/MS method for the determination of valsartan to investigate the pharmacokinetics of valsartan tablets in the fasted and fed states. METHODS The separation was achieved on a Waters Symmetry C18 column (3.9 mm×150 mm, 5 μm) with mobile phase consisting of methanol -10 mmoL·L-1 ammonium acetate and 0.05% formic acid aqueous solution (70/30, V/V). Twelve healthy subjects were divided into two groups by randomized blind design. These two groups were administered single dose of 80 mg valsartan tablets for single dose pharmacokinetics profile at fasted and fed states respectively. The plasma concentrations of valsartan were measured by LC-MS/MS. RESULTS The calibration curve of valsartan in human plasma was linear over the concentration rang of 10.00-5 000 ng·mL-1. In the fasted state, the main pharmacokinetic parameters of valsartan were as follows: ρmax were (3 156±869)ng·mL-1,AUC0-24 h were (20 181±3 535)ng·h·mL-1,AUC0-∞ were (20 576±3 540)ng·h·mL-1, t1/2 were (6.72±1.25)h,tmax were (3.67±0.98)h. In the fed state, the main pharmacokinetic parameters of valsartan were as follows: ρmax were (2 502±508)ng·mL-1,AUC0-24 h were (14 654±3 715)ng·h·mL-1,AUC0-∞ were (14 816±3 681) ng·h·mL-1,t1/2 were (5.84±2.14)h,tmax were (3.75±1.48)h. CONCLUSION The method is proved to be convenient, accurate and sensitive, and suitable for the pharmacokinetic study of 80 mg valsartan tablets in healthy Chinese volunteers after being fasted and fed. The result suggests that high fat and calories diet has effect on the pharmacokinetics of valsartan tablets. A high fat and calories diet before the oral administration of 80 mg valsartan tablets results in a lower ρmax by 20.72% and AUC0-24 h by 27.39%. There is no significant difference in tmax.
关键词
缬沙坦 /
药动学 /
高脂高热量饮食 /
液质联用法 /
食品药物相互作用
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Key words
valsartan /
pharmacokinetics /
high fat and calories diet /
LC-MS/MS /
food-drug interaction
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中图分类号：
R284
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参考文献
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脚注
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基金
苏州市药学会-江苏恒瑞临床药学科研基金项目资助(Syhky201807)
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