Pharmacokinetic Properties of Lansoprazole (30-mg Enteric-Coated Capsules) and Its Metabolites: A Single-Dose, Open-Label Study in Healthy Chinese Male Subjects

摘要

BACKGROUND: 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.OBJECTIVES: 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.METHODS: 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 C_max,T_max,elimination t_1/2 [t_1/2z], mean residence time [MRT], AUC_0-24, AUC0_infinity, apparent oral clearance [CL_z/F], and apparent volume of distribution [V_z/F]) were determined using the noncompartmental method.RESULTS: 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: C-max, 1047 (344) ng/mL; T_max, 2.0 (0.7) hours; t_1/2z 2.24 (1.43) hours; MRT, 3.62 (0.87) hours; AUC_0-24, 3388 (1484) ng/mL/h; AUC_0-infinity, 3496 (1693) ng/mL/h; CL_z/F, 9.96 (3.74) L/h; and V_z/F, 32.83 (11.74) L. The findings with 5'-hydroxy lansoprazole and lansoprazole sulfone, respectively, were as follows: C_max, 111.2 (41.8) and 66.6 (52.9) ng/mL; T_max, 2.1 (0.8) and 1.9 (0.8) hours; t_1/2z, 2.31 (1.18) and 2.52 (1.54) hours; and AUC_0-24, 317.0 (81.2) and 231.9 (241.7) ng/mL/h. No adverse events were reported throughout the study.CONCLUSIONS: In these healthy Chinese male volunteers administered a single oral dose of lansoprazole 30 mg, absorption of lansoprazole was rapid (mean C_max, 1047 ng/mL; T_max, ~2.0 hours). Its 2 primary active metabolites, 5'-hydroxy lansoprazole and lansoprazole sulfone, were identified in measurable quantities in plasma (C_max, 111.2 and 66.6 ng/mL, respectively; and T_max, 2.1 and 1.9 hours). The plasma t_1/2z did not appear to reflect the duration of suppression of gastric acid secretion: the t_1/2z values of lansoprazole and the 2 metabolites were ~2 to 2.5 hours, while the acid-inhibitory effect lasted >24 hours. C_max, AUC, and t_1/2z 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.