HPLC-MS/MS法测定雷诺嗪血药浓度及其缓释制剂的药代动力学研究

中国临床药理学与治疗学 ›› 2012, Vol. 17 ›› Issue (5): 549-553.

HPLC-MS/MS法测定雷诺嗪血药浓度及其缓释制剂的药代动力学研究

谭亲友^1,2, 朱荣华¹, 李焕德¹, 张啟智^1,2, 方平飞¹, 颜苗¹, 彭文兴¹

¹中南大学湘雅二医院临床药学教研室,长沙 410011,湖南;
²中南大学药学院,长沙 410013,湖南

收稿日期:2011-12-15 修回日期:2012-04-03 出版日期:2012-05-26 发布日期:2012-05-28
通讯作者: 李焕德,男,教授,博士生导师,主要从事体内药物分析与临床药物动力学研究。Tel: 0731-84436720 E-mail: tqy1013@163.com
作者简介:谭亲友,男,博士研究生,主管药师,主要从事体内药物分析与临床药物动力学研究。Tel: 13574124058 E-mail: dongkou@126.com

Quantification of Ranolazine in human plasma using HPLC-MS/MS for pharmacokinetic study of its sustained-release preparation

TAN Qin-you^1,2, ZHU Rong-hua¹, LI Huan-de¹, ZHANG Qi-zhi^1,2, FANG Ping-fei¹, YAN Miao¹, PENG Wen-xing¹

¹The Clinical Pharmacy & Pharmacology Research Institute, Second Xiangya Hospital, Central South University, Changsha 410011,Hunan,China;
²Pharmaceutical Science of Centre South University, Changsha 410013,Hunan,China

Received:2011-12-15 Revised:2012-04-03 Online:2012-05-26 Published:2012-05-28

摘要/Abstract

摘要： 目的:通过方法学的建立和确认,进行了单次给药雷诺嗪缓释片后的药动学研究,为该药临床研究及合理用药提供依据。方法: 12名健康受试者,男女各半,采用三周期、3交叉(3×3)拉丁方设计,实验分别单剂量给500、1000、1500 mg 雷诺嗪缓释片。分别于给药前(0 h)和给药后 0.5、1.0、2.0、2.5、3.0、3.5、4.0、5.0、6.0、8.0、10.0、12.0、16.0、24.0、36.0、48.0 h 采集静脉血 4 mL。采用LC-MS/MS法测定血浆样品中雷诺嗪的浓度,并计算主要的药动学参数。结果: 单剂量给药500、1000、1500 mg 雷诺嗪缓释片后C_max分别为(742±253)、(1355±502)和(2329±890) ng/mL;AUC_0-48分别为(9072±3400)、(16574±6806)和(29324±10857)ng·mL^-1·h;AUC_0-∞ 分别为(9827±3152)、(16882±6791) 和(29924±10706) ng·mL^-1·h;t_max分别为(5.3±1.4),(4.2±1.2)和(5.9±2.8) h;t_1/2分别为(6.4±3.3),(6.4±3.5)和(6.7±4.3) h。结论:在本次实验中,C_max 和AUC 与剂量成比例增加,单次给药3个剂量有很好的线性关系,所有受试者都有较好的耐受性。

关键词: 雷诺嗪, 药代动力学, 液相色谱-串联质谱

Abstract: AIM: The LC-MS/MS method was developed and validated,and assessed the pharmacokinetic properties after a single dose of 500, 1000, or 1500 mg of ranolazine in healthy Chinese volunteers.METHODS: Twelve Chinese subjects (6 men, 6 women) were enrolled in the single-dose phase of the PK study. The study were assigned to open-label, randomized-sequence, 3×3 latin square design which consisted of three 1-day treatment periods and two 7-day washout periods.Volunteers were randomly allocated to receive a single dose of 500, 1000, or 1500 mg of ranolazine (sustained-release tablets), sequential blood samples (4 mL each) were collected into heparin tubes at 0 hour (before administration) and 0.5, 1.0, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0, 36.0,and 48.0 hours after administration. The LC-MS/MS method was developed and validated.RESULTS:The main PK parameters for ranolazine after administration of a single oral dose of 500, 1000, and 1500 mg were as follows: C_max were (742±253), (1355±502), and (2329±890) ng/mL, respectively; AUC_0-48 were (9072±3400), (16574 ± 6806) , and (29324±10857) ng·mL^-1·h,AUC_0-∞ were (9827±3152),(16882±6791), and (29924±10706) ng·mL^-1·h; t_max were (5.3±1.4), (4.2±1.2), and (5.9±2.8) hours; t_1/2 were (6.4±3.3), (6.4±3.5), and (6.7±4.3) hours.CONCLUSION: In this group of healthy Chinese subjects, AUC and C_max increased proportionally with the dose, the PK properties of ranolazine were linear after administration of single oral doses of 500 to 1500 mg.These dosages were generally well tolerated by all the subjects.

Key words: Ranolazine, Pharmacokinetics , LC-MS/MS

中图分类号:

R969.1

谭亲友, 朱荣华, 李焕德, 张啟智, 方平飞, 颜苗, 彭文兴. HPLC-MS/MS法测定雷诺嗪血药浓度及其缓释制剂的药代动力学研究[J]. 中国临床药理学与治疗学, 2012, 17(5): 549-553.

TAN Qin-you, ZHU Rong-hua, LI Huan-de, ZHANG Qi-zhi, FANG Ping-fei, YAN Miao, PENG Wen-xing. Quantification of Ranolazine in human plasma using HPLC-MS/MS for pharmacokinetic study of its sustained-release preparation[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2012, 17(5): 549-553.

参考文献

[1] Chaitman BR.Ranolazine for the treatment of chronic angia and potential use in other cardiovascular conditions[J]. Circulation, 2006, 113(20):2462-2472.
[2] Cooper-DeHoff R, Pepine CJ.Ranolazine is associated with cardiovascular and metabolic improvement: a win-win for patients with diabetes[J]. Eur Heart J, 2006, 27(1):5-6.
[3] Antzelevitch C, Belardinelli L, Zygmunt AC, et al. Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties[J]. Circulation, 2004, 110(8): 904-910.
[4] Cocco G, Rousseau MF, Bouvy T, et al. Effects of a new metabolic modulator, ranolazine, on exercise tolerance in angina pectoris patients treated with beta-blocker or diltiazem[J]. J Cardiovasc Pharmacol, 1992, 20(1):131-138.
[5] Beinart SC, Sales AE, Spertus JA, et al. Impact of angina burden and other factors on treatment satisfaction after acute coronary syndromes[J]. Am Heart J, 2003, 146(4):646-652.
[6] Chaitman BR, Skettino SL, Parker JO, et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina[J]. J Am Coll Cardiol, 2004,43(8):1375-1382.
[7] Rousseau MF, Pouleur H, Cocco G, et al. Comparative efficacy of ranolazine versus atenolol for chronic angina pectoris[J]. Am J Cardiol, 2005, 95(3) :311-316.
[8] Liang Y, Xie L, Liu XD,et al.Simple, sensitive and rapid liquid chromatography/atmospheric pressure chemical ionization mass spectrometric method for the quantitation of Ranolazine in rat plasma[J]. Rapid Commun Mass Spectrom, 2006, 20(4):523-528.
[9] Zhong J, Liu XQ , Chen Y, et al. Determination of ranolazine in rat plasma by liquid chromatography-electrospray ionization mass spectrometry[J].Chromatographia,2006, 63(3):123-127.
[10] 李玲,谭志荣,陈尧,等.快速灵敏的LC-MS/MS法测定人血浆中缬沙坦浓度[J].中国临床药理学和治疗学, 2010, 11(7):809-813.
[11] Markus Jerling. Clinical Pharmacokinetics of Ranolazine[J]. Clin Pharmacokinet, 2006,45(5):469-491.

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