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目的:建立血浆和尿液中兰索拉唑及其游离型代谢物5-羟基兰索拉唑和兰索拉唑砜浓度的LC-MS/MS测定法,研究注射用兰索拉唑在健康受试者体内的药代动力学。方法:采用开放、自身对照三周期试验设计,12名健康受试者(6男6女)随机分成3组,分别静脉滴注单剂量15、30、45 mg或连续7 d多剂量30 mg注射用兰索拉唑,0~12 h内间隔采集血样,0~24h分段采集尿样,LC-MS/MS法进行测定,DAS2.0软件估算药动学参数。结果:建立的LC-MS/MS法在血浆兰索拉唑浓度10~4000μg·L-1、5-羟基兰索拉唑浓度2~400μg·L-1、兰索拉唑砜浓度1~400μg·L-1及尿液兰索拉唑浓度4~3200μg·L-1、5-羟基兰索拉唑浓度0.8~320μg·L-1、兰索拉唑砜浓度0.4~320μg·L-1的范围内线性关系良好,批间及批内精密度RSD均小于15%。单剂量给药30 mg后的主要药动学参数如下:兰索拉唑、5-羟基兰索拉唑和兰索拉唑砜的Cmax分别为(1562±276)μg·L-1、(124.3±59.1)μg·L-1和(66.03±27.3)μg·L-1,tmax分别为(0.52±0.050)h、(2.13±0.73)h和(0.67±0.13)h,AUC0-τ分别为(2894±516)μg·L-1·h、(261.3±86.0)μg·L-1·h和(121.8±36.7)μg·L-1·h,t1/2分别为(1.56±0.31)h、(2.13±0.73)h和(1.49±0.40)h;多剂量给药后,兰索拉唑、5-羟基兰索拉唑和兰索拉唑砜的Cmax分别为(1555±403)μg·L-1、(101.5±28.0)μg·L-1和(81.06±37.5)μg·L-1,Cmin分别为(14.59±4.126)μg·L-1、(3.131±0.82)μg·L-1和(1.046±0.61)μg·L-1,tmax分别为(0.53±0.070)h、(0.67±0.14)h和(0.70±0.17)h,AUC0-τ分别为(3031±830)μg·L-1·h、(244.4±62.5)μg·L-1·h和(166.5±84.4)μg·L-1·h,t1/2分别为(1.68±0.39)h、(2.01±0.65)h和(1.51±0.35)h。尿液中仅测得5-羟基兰索拉唑,其0~24 h的尿药累积排泄率约为(2.7!1.2)%;15~45 mg范围单次给药具有线性药动学特征;且未见性别差异;连续给药无蓄积作用。但是试验中发现1名受试者对兰索拉唑代谢的明显异常(不参与统计)。结论:建立的LC-MS/MS测定法准确可靠,兰索拉唑存在代谢多态性,临床应注意个体化用药。
OBJECTIVE: To establish a LC-MS / MS method for the determination of lansoprazole and its free metabolites 5-hydroxy-lansoprazole and lansoprazole-sulfone in plasma and urine, and to study the effect of lansoprazole for injection on health Pharmacokinetics in subjects. Methods: A three-period, open-label, self-controlled trial was designed. Twelve healthy subjects (6 males and 6 females) were randomly divided into 3 groups: single dose of 15, 30, 45 mg or multiple doses of 30 mg Lansoprazole was used to collect blood samples within 0 ~ 12 h intervals and urine samples were collected 0 ~ 24 h by LC-MS / MS method. Pharmacokinetic parameters were estimated by DAS2.0 software. Results: The established LC-MS / MS method was used to determine the plasma concentration of lansoprazole at concentration of 10 ~ 4000μg · L-1, 5-hydroxyl-lansoprazole 2 ~ 400μg · L-1, L-1 and urine lansoprazole concentration of 4 ~ 3200μg · L-1, 5-hydroxy-lansoprazole concentration of 0.8 ~ 320μg · L-1, lansoprazole sulfone concentration of 0.4 ~ 320μg · L-1 The linearity within the range was good, with inter-lot and intra-batch precision RSDs less than 15%. The main pharmacokinetic parameters of single dose of 30 mg were as follows: Cmax of lansoprazole, 5-hydroxy-lansoprazole and lansoprazole sulfone were (1562 ± 276) μg · L-1, (124.3 (0.52 ± 0.050) h, (2.13 ± 0.73) h and (0.67 ± 0.13) h, respectively, and AUC0-τ were (± 59.1) μg · L-1 and (66.03 ± 27.3) μg · L- (1.56 ± 0.31) h, (2894 ± 516) μg · L-1 · h, (261.3 ± 86.0) μg · L-1 · h and (121.8 ± 36.7) μg · L-1 · h, (2.13 ± 0.73) h and (1.49 ± 0.40) h, respectively. After multiple doses, the Cmax of lansoprazole, 5-hydroxylan lansoprazole and lansoprazole sulfone were (1555 ± 403) μg · L (101.5 ± 28.0) μg · L-1 and (81.06 ± 37.5) μg · L-1, respectively, and the values of Cmin were (14.59 ± 4.126) μg · L-1 and (3.131 ± 0.82) μg · L- (1.046 ± 0.61) μg · L-1, tmax were (0.53 ± 0.070) h, (0.67 ± 0.14) h and (0.70 ± 0.17) h respectively, and AUC0-τ were (3031 ± 830) μg · L- · H, (244.4 ± 62.5) μg · L-1 · h and (166.5 ± 84.4) μg · L-1 · h and t1 / 2 were 1.68 ± 0.39 h, 2.01 ± 0.65 h and 1.51 ± 0.35) h. Only 5-hydroxy-lansoprazole was detected in the urine, and cumulative excretion rate of urine from 0 to 24 h was about (2.7¡À1.2)%. Single-dose administration in the range of 15-45 mg had linear pharmacokinetic characteristics. And no gender differences; continuous administration without accumulation. However, one subject was found to have significant abnormalities in Lansoprazole metabolism (not included in the statistics). Conclusion: The established LC-MS / MS method is accurate and reliable, and the polymorphism of lansoprazole exists. Clinical should pay attention to individualized medication.