Song Min, Gao Xuan, Hang Tai-Jun, Wen Ai-Dong
Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, People's Republic of China.
Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
Curr Ther Res Clin Exp. 2009 Jun;70(3):228-39. doi: 10.1016/j.curtheres.2009.05.002.
Lansoprazole, a benzimidazole derivative, is indicated for the treatment of various peptic diseases. It is metabolized mainly in the liver, and its primary active metabolites present in plasma are 5'-hydroxy lansoprazole and lansoprazole sulfone. Few data are available on the pharmacokinetic properties of lansoprazole, 5'-hydroxy lansoprazole, and lansoprazole sulfone, which can be used to measure cytochrome P450 (CYP) 2C19 activity.
The aims of this study were to investigate the clinical plasma pharmacokinetic properties of lansoprazole and its metabolites in healthy Chinese male volunteers, and to assess the influences of CYP2C19 on the pharmacokinetics of lansoprazole.
Healthy adult Chinese male volunteers were enrolled in this single-dose, open-label study. All patients received a single oral enteric capsule containing 30 mg of lansoprazole after a 12-hour overnight fast. Serial blood samples were collected immediately before (0 hour) and at 20, 40, 60, 90, 120, and 150 minutes and 3, 4, 6, 8, 10, 12, 15, and 24 hours after study drug administration. The plasma concentrations of lansoprazole, 5'-hydroxy lansoprazole, and lansoprazole sulfone were determined using a validated internal standard high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. Pharmacokinetic properties (including Cmax, Tmax, elimination t½ [t½z], mean residence time [MRT], AUC0-24, AUC0-∞, apparent oral clearance [CLz/F], and apparent volume of distribution [Vz/F]) were determined using the noncompartmental method.
Twenty volunteers (mean [SD] age, 34.9 [2.9] years; weight, 64.6 [2.2] kg; height, 171.3 [3.3] cm) were enrolled in and completed the study. The mean (SD) pharmacokinetic properties of lansoprazole were as follows: Cmax, 1047 (344) ng/mL; Tmax, 2.0 (0.7) hours; t½z, 2.24 (1.43) hours; MRT, 3.62 (0.87) hours; AUC0-24, 3388 (1484) ng/mL/h; AUC0-∞, 3496 (1693) ng/mL/h; CLz/F, 9.96 (3.74) L/h; and Vz/F, 32.83 (11.74) L. The findings with 5'-hydroxy lansoprazole and lansoprazole sulfone, respectively, were as follows: Cmax, 111.2 (41.8) and 66.6 (52.9) ng/mL; Tmax, 2.1 (0.8) and 1.9 (0.8) hours; t½z, 2.31 (1.18) and 2.52 (1.54) hours; and AUC0-24, 317.0 (81.2) and 231.9 (241.7) ng/mL/h. No adverse events were reported throughout the study.
In these healthy Chinese male volunteers administered a single oral dose of lansoprazole 30 mg, absorption of lansoprazole was rapid (mean Cmax, 1047 ng/mL; Tmax, ~2.0 hours). Its 2 primary active metabolites, 5'-hydroxy lansoprazole and lansoprazole sulfone, were identified in measurable quantities in plasma (Cmax, 111.2 and 66.6 ng/mL, respectively; and Tmax, 2.1 and 1.9 hours). The plasma t½z did not appear to reflect the duration of suppression of gastric acid secretion: the t½z values of lansoprazole and the 2 metabolites were ~2 to 2.5 hours, while the acid-inhibitory effect lasted >24 hours. Cmax, AUC, and t½z of lansoprazole, and especially lansoprazole sulfone, varied. Differences in metabolism types and/or genotype of CYP2C19 should be taken into account when planning a lansoprazole dosing regimen.
兰索拉唑是一种苯并咪唑衍生物，用于治疗各种消化性疾病。它主要在肝脏中代谢，血浆中存在的主要活性代谢产物是5'-羟基兰索拉唑和兰索拉唑砜。关于兰索拉唑、5'-羟基兰索拉唑和兰索拉唑砜的药代动力学特性的数据较少，这些数据可用于测量细胞色素P450（CYP）2C19活性。
本研究的目的是调查兰索拉唑及其代谢产物在健康中国男性志愿者中的临床血浆药代动力学特性，并评估CYP2C19对兰索拉唑药代动力学的影响。
健康成年中国男性志愿者参加了这项单剂量、开放标签研究。所有患者在禁食12小时过夜后口服一粒含30 mg兰索拉唑的肠溶胶囊。在给药前（0小时）以及给药后20、40、60、90、120和150分钟以及3、4、6、8、10、12、15和24小时立即采集系列血样。采用经过验证的内标高效液相色谱-串联质谱（HPLC-MS/MS）法测定兰索拉唑、5'-羟基兰索拉唑和兰索拉唑砜的血浆浓度。使用非房室模型方法确定药代动力学特性（包括Cmax、Tmax、消除半衰期[t½z]、平均驻留时间[MRT]、AUC0-24、AUC0-∞、表观口服清除率[CLz/F]和表观分布容积[Vz/F]）。
20名志愿者（平均[标准差]年龄34.9[2.9]岁；体重64.6[2.2]kg；身高171.3[3.3]cm）入组并完成研究。兰索拉唑的平均（标准差）药代动力学特性如下：Cmax为1047（344）ng/mL；Tmax为2.0（0.7）小时；t½z为2.24（1.43）小时；MRT为3.62（0.87）小时；AUC0-24为3388（1484）ng/mL/h；AUC0-∞为3496（1693）ng/mL/h；CLz/F为9.96（3.74）L/h；Vz/F为32.83（11.74）L。5'-羟基兰索拉唑和兰索拉唑砜的结果分别如下：Cmax为111.2（41.8）和66.6（52.9）ng/mL；Tmax为2.1（0.8）和1.9（0.8）小时；t½z为2.31（1.18）和2.52（1.54）小时；AUC0-24为317.0（81.2）和231.9（241.）ng/mL/h。整个研究期间未报告不良事件。
在这些单次口服30 mg兰索拉唑的健康中国男性志愿者中，兰索拉唑吸收迅速（平均Cmax为1047 ng/mL；Tmax约为2.0小时）。其两种主要活性代谢产物5'-羟基兰索拉唑和兰索拉唑砜在血浆中可检测到（Cmax分别为111.2和66.6 ng/mL；Tmax为2.1和1.9小时）。血浆t½z似乎未反映胃酸分泌抑制的持续时间：兰索拉唑及其两种代谢产物的t½z值约为2至2.5小时，而抑酸作用持续>24小时。兰索拉唑尤其是兰索拉唑砜的Cmax、AUC和t½z存在差异。在制定兰索拉唑给药方案时应考虑CYP2C19代谢类型和/或基因型的差异。
