注射用兰索拉唑在健康受试者体内的药代动力学研究

Pharmacokinetics of lansoprazole for injection in healthy volunteers

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 an LC- MS /MS method for the determination of lansoprazole and its non- conjugated metabolites,5- hydroxy lansoprazole and lansoprazole sulphone in plasma and urine for the pharmacokinetic study of lansoprazole for injection in healthy Chinese volunteers. Methods： In a randomized,open label,three- way crossover study,12 healthy volunteers（ 6 male and 6 female） were divided into three groups and administrated intravenously with a single dose of 15,30 and 45 mg of lansoprazole for injection,respectively,or multiple 30 mg doses for 7 consecutive days. The blood samples were collected at predetermined time points from 0 to 12 h and the urine samples in intervals from 0 to 24 h,and determined by the LC- MS /MS method. The pharmacokinetic parameters were estimated by DAS2. 0 software. Results： The LC- MS /MS method established showed linear calibration in the ranges of 10- 4000 μg·L- 1,2-400 μg·L- 1and 1- 400 μg·L- 1for lansoprazole,5- hydroxyl lansoprazole and lansoprzole sulphone in human plasma,respectively,and 4- 3200 μg·L- 1,0.8-320 μg·L- 1and 0. 4- 320μg·L- 1for lansoprazole,5- hydroxyl lansoprazole and lansoprzole sulphone in human urine,respectively. The intra- and inter- batch standard deviations were both less than 15%. After a single administration of 30 mg lansoprazole,the mean pharmacokinetic properties of lansoprazole,5- hydroxyl lansoprazole and Lansoprazole sulphone were as follows： Cmax（ 1562 ±276） μg·L- 1,（ 124.3 ±59.1） μg·L- 1and（ 66. 03 ± 27. 3） μg·L- 1,respectively; tmax（ 0.52 ±0. 050） h,（ 2. 13 ±0.73） h and（ 0.67 ±0.13） h,respectively; AUC0- τ（ 2894 ±516） μg·L- 1·h,（ 261. 3 ± 86. 0） μg·L- 1·h and（ 121. 8 ±36. 7） μg·L- 1·h,respectively; t1 /2（ 1. 56 ±0. 31） h,（ 2. 13 ±0. 73） h and（ 1. 49 ± 0. 40） h,respectively. After multiple administrations of 30 mg lansoprazole,the mean pharmacokinetic properties of lansoprazole,5- hydroxyl lansoprazole and lansoprazole sulphone were as follows： Cmax（ 1555± 403） μg·L- 1,（ 101.5 ±28.0） μg·L- 1and（ 81. 06 ± 37. 5） μg·L- 1,respectively; Cmin（ 14.59 ±4. 126）μg·L- 1,（ 3.131 ±0.82） μg·L- 1and（ 1. 046 ± 0. 61） μg·L- 1,respectively; tmax（ 0.53 ±0.070） h,（ 0. 67 ±0. 14） h and（ 0. 70 ± 0. 17） h,respectively; AUC0- τ（ 3031 ±830） μg·L- 1·h,（ 244. 4 ±62. 5） μg·L- 1·h and（ 166. 5 ± 84. 4） μg·L- 1·h,respectively; t1 /2（ 1.68 ±0.39） h,（ 2.01 ±0.65） h and（ 1. 51 ±0.35） h,respectively. Only non- conjugated 5- hydroxy lansoprazole was found in urine with a cumulative excretory amount of（ 2. 7 !1. 2） % in 24 hours. Linear pharmacokinetics was found after single intravenous dose of lansoprazole in the range of 15 mg to 45 mg without obvious gender differences. No cumulative effect was found after multiple 30 mg doses for 7 consecutive days. But one volunteer was found to have significantly different pharmacokinetic behavior（ not included for ANOVA） from the others. Conclusion： The LC- MS /MS method established was accurate and suitable for the pharmacokinetic study of lansoprazole for injection. There was polymorphism in the metabolism of lansoprazole,therefore,therapeutic drug monitoring and individualized medication should be conducted for Lansoprazole clinical application.