Shang De-Wei, Wang Zhan-Zhang, Hu Hai-Tang, Zhang Yue-Feng, Ni Xiao-Jia, Lu Hao-Yang, Zhang Ming, Hu Jin-Qing, Qiu Chang, Peng Huan, Shen Ling-Fang, Wen Yu-Guan
The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), 36 Mingxin Road, Guangzhou, 510370, China.
Clinical Research Center, Livzon Pharmaceutical Group Co., Ltd., 132 Guihua North Road, Zhuhai, 519020, China.
Eur J Clin Pharmacol. 2018 Jan;74(1):61-67. doi: 10.1007/s00228-017-2340-1. Epub 2017 Oct 3.
The purpose of this study was to investigate the potential effects of a meal and grapefruit juice on the pharmacokinetics of blonanserin and its metabolite N-desethyl blonanserin in healthy Chinese volunteers.
This was a single-centre, open-label, fixed-sequence study, where 12 healthy Chinese volunteers received a single dose of 8 mg blonanserin after an overnight fast in period 1 (reference), a high-fat meal during period 2 and with co-administration of 250 mL of grapefruit juice in period 3. The washout period was 7 days. Series of plasma samples were collected after each dose to determine concentrations of blonanserin and its metabolite N-desethyl blonanserin using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated by non-compartmental analysis and compared between periods by standard average bioequivalence ANOVA. Adverse events were monitored throughout the study.
All subjects completed the study. High-fat meals significantly increased blonanserin exposure (AUC) 2.58-fold (90% CI 2.21, 3.02), relative to the reference period. Co-administration of blonanserin with grapefruit juice remarkably prolonged elimination half-life of blonanserin (from 9.7 to 21.4 h) and significantly increased exposures to blonanserin and N-desethyl blonanserin by 5.82-fold (90% CI 4.57, 7.42) and 1.81-fold (90% CI 1.65, 1.98), respectively.
These results suggested that blonanserin was largely metabolised in the intestinal tract before becoming systemically available, and both food and grapefruit juice enhanced exposure to blonanserin and N-desethyl blonanserin. Grapefruit juice increased bioavailability and may have reduced systemic clearance of blonanserin. Further intestinal CYP3A4 and hepatic CYP3A4 might be postulated to explain the delayed elimination of blonanserin. Dose adjustment of blonanserin is needed on the basis of co-intake of known strong CYP3A4 inhibitor. Patients taking high-dose blonanserin also need to be cautious about the ingestion of grapefruit juice.
本研究旨在探讨进餐和葡萄柚汁对健康中国志愿者中布南色林及其代谢产物N-去乙基布南色林药代动力学的潜在影响。
这是一项单中心、开放标签、固定顺序研究，12名健康中国志愿者在第1阶段（参照期）空腹过夜后接受8 mg布南色林单次给药，在第2阶段进食高脂餐，在第3阶段同时给予250 mL葡萄柚汁。洗脱期为7天。每次给药后采集一系列血浆样本，采用液相色谱-串联质谱法测定布南色林及其代谢产物N-去乙基布南色林的浓度。通过非房室分析估算药代动力学参数，并通过标准平均生物等效性方差分析在各阶段之间进行比较。在整个研究过程中监测不良事件。
所有受试者均完成研究。相对于参照期，高脂餐使布南色林的暴露量（AUC）显著增加2.58倍（90% CI 2.21, 3.02）。布南色林与葡萄柚汁同时给药显著延长了布南色林的消除半衰期（从9.7小时延长至21.4小时），并使布南色林和N-去乙基布南色林的暴露量分别显著增加5.82倍（90% CI 4.57, 7.42）和1.81倍（90% CI 1.65, 1.98）。
这些结果表明，布南色林在全身可用之前大部分在肠道中代谢，食物和葡萄柚汁均增加了布南色林和N-去乙基布南色林的暴露量。葡萄柚汁增加了生物利用度，可能降低了布南色林的全身清除率。推测肠道CYP3A4和肝脏CYP3A4可能解释布南色林消除延迟的现象。基于已知强效CYP3A4抑制剂的共同摄入情况，需要调整布南色林的剂量。服用高剂量布南色林的患者也需要谨慎摄入葡萄柚汁。
