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目的:建立同时测定人血浆中贝那普利及贝那普利拉浓度的超液相色谱-串联质谱法(UPLC-MS/MS),研究中国健康志愿者单次口服氨氯地平贝那普利胶囊后贝那普利及其活性代谢物贝那普利拉的药动学特征。方法:24名健康受试者随机分成3组,每组8人,男女各半,分别单次口服贝那普利含量为10,20,30 mg氨氯地平贝那普利胶囊。血浆样品用乙腈进行蛋白沉淀,贝那普利及贝那普利拉的血浆浓度采用超高效液相色谱-串联质谱法检测。结果:贝那普利及贝那普利拉在1.0～1 000.0ng.mL-1范围内线性关系良好。单次口服10,20,30 mg贝那普利剂量后tmax分别为(0.50±0.19),(0.81±0.51),(0.63±0.40)h;Cmax分别为(264.1±85.0),(376.8±173.6),(642.4±331.1)ng.mL-1,AUC0-8分别为(245.9±87.7),(450.5±122.8),(557.6±73.5)ng.h.mL-1,AUC0-∞分别为(248.7±87.9),(477.2±130.8),(580.2±71.1)ng.h.mL-1。t1/2分别为(0.76±0.19),(2.8±1.7),(2.91±1.65)h,V/F分别为(47.2±12.8),(186.6±128.8),(217.9±122.6)L,MRT0-8分别为(1.0±0.3),(2.3±0.7),(1.8±0.6)h。CL/F分别为(44.5±14.7),(44.6±11.3),(52.5±7.7)L.h-1;单次口服10,20,30 mg贝那普利剂量后贝那普利拉的tmax分别为(1.4±0.5),(2.1±1.3),(1.4±0.4 h);Cmax分别为(232.6±100.5),(323.5±61.6),(615.9±188.2)ng.mL-1,AUC0-24分别为(1025.9±172.2),(1924.8±314.4),(3095.1±713.4)ng.h.mL-1,AUC0-∞分别为(1053.6±177.1),(1 989.8±320.9),(3 150.0±715.6)ng.h.mL-1。t1/2分别为(4.9±0.3),(5.0±0.7),(4.3±0.4)h;V/F分别为(69.3±11.5),(75.0±16.5),(62.0±13.8)L;CL/F分别为(9.7±1.6),(10.3±1.4),(9.9±2.0)L.h-1;MRT0-24分别为(5.9±1.0),(6.7±1.1),(5.5±0.9)h。结论:所建立的方法灵敏,准确,快捷,适合于贝那普利临床药动学研究。在10～30 mg剂量范围内、贝那普利符合线性药动学特征,贝那普利拉的AUC与贝那普利剂量呈正比关系,健康受试者能安全耐受。
OBJECTIVE: To establish a simultaneous determination of benazepril and benazeprim in human plasma by UPLC-MS / MS, and to study the effect of single oral amlodipine benazepril on Chinese healthy volunteers Pharmacokinetic characteristics of benazepril and its active metabolite benazeprilat. Methods: Twenty-four healthy subjects were randomly divided into 3 groups, 8 in each group, with half male and half female. The benazepril capsules containing benazepine in a single dose of 10, 20 and 30 mg were orally administered respectively. Plasma samples were subjected to protein precipitation with acetonitrile. Plasma concentrations of benazepril and benazeprilat were determined by ultra performance liquid chromatography-tandem mass spectrometry. Results: Benazepril and benazeprilat showed good linearity in the range of 1.0-1 000.0 ng.mL-1. After a single oral dose of 10,20,30 mg benazepril, tmax was (0.50 ± 0.19), (0.81 ± 0.51), (0.63 ± 0.40) h respectively; Cmax was (264.1 ± 85.0), (376.8 ± 173.6 (642.4 ± 331.1) ng.mL-1 and AUC0-8 were (245.9 ± 87.7), (450.5 ± 122.8) and (557.6 ± 73.5) ng.h.mL-1 respectively. The AUC0- ± 87.9), (477.2 ± 130.8), (580.2 ± 71.1) ng.h.mL-1. t1 / 2 were (0.76 ± 0.19), (2.8 ± 1.7), (2.91 ± 1.65) h and V / F were 47.2 ± 12.8, 186.6 ± 128.8 and 217.9 ± 122.6, respectively. MRT0- 8 were (1.0 ± 0.3), (2.3 ± 0.7), (1.8 ± 0.6) h respectively. (44.5 ± 14.7), (44.6 ± 11.3) and (52.5 ± 7.7) Lh-1, respectively. The tmax of benazeprilat after a single oral dose of 10,20,30 mg benazepril was (1.4 ± 0.5), (2.1 ± 1.3) and (1.4 ± 0.4 h), respectively; Cmax were (232.6 ± 100.5), (323.5 ± 61.6) and (615.9 ± 188.2) ng.mL- (1025.9 ± 172.2), (1924.8 ± 314.4) and (3095.1 ± 713.4) ng.h.mL-1, and the AUC0-∞ were (1053.6 ± 177.1), (988.8 ± 320.9), (3 150.0 ± 715.6) ng .h.mL-1. t1 / 2 were (4.9 ± 0.3), (5.0 ± 0.7) and (4.3 ± 0.4) h respectively; V / F were 69.3 ± 11.5 and 75.0 ± 16.5 and 62.0 ± 13.8, F were (9.7 ± 1.6), (10.3 ± 1.4) and (9.9 ± 2.0) Lh-1 respectively; MRT0-24 were (5.9 ± 1.0), (6.7 ± 1.1) and (5.5 ± 0.9) h, respectively. Conclusion: The established method is sensitive, accurate and rapid, and is suitable for clinical pharmacokinetic study of benazepril. In the dose range of 10-30 mg, benazepril conforms to the linear pharmacokinetic profile, and the beneprofen AUC is in direct proportion to the benazepril dose and is safe for healthy subjects.