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

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

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、1500mg雷诺嗪缓释片。分别于给药前(0h)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、48.0h采集静脉血4mL。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、1500mg雷诺嗪缓释片后Cmax分别为(742±253)、(1355±502)和(2329±890)ng/mL;AUC0-48分别为(9072±3400)、(16574±6806)和(29324±10857)ng.mL-1.h;AUC0-∞分别为(9827±3152)、(16882±6791)和(29924±10706)ng.mL-1.h;tmax分别为(5.3±1.4),(4.2±1.2)和(5.9±2.8)h;t1/2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,Cmax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。

ABSTRACT AIM.. The LC-MS/MS method was developed and validated, and assessed the pharmacokinetic properties a{ter a single dose of 500, 1000, or 1500 mg of ranolazine in healthy Chinese volunteers. METHODS： Twelve Chi- nese subjects （6 men, 6 women） were enrolled in the single-dose phase of the PK study. Thestudy were assigned to open-label, randomized- sequence, 3 × 3 latin square design which consis- ted 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 tab- lets）, sequential blood samples （4 mL each） were collected into heparin tubes at 0 hour （be- fore 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 adminis- tration. The LC-MS/MS method was developed and validated. RESULTS. The main PK parame- ters for ranolazine after administration of a sin-gle oral dose of 500, 1000, and 1500 mg were as follows： Cmax were （742±253）, （1355±502）, and （2329±890） ng/mL, respectively; AUG0-48 were （9072±3400）, （16574 ± 6806） , and （29324±10857） ng. mL^-1·h, AUC0-∞ were （9827±3152）,（16882±6791）, and （29924±10706） ng. mL^-1·h; tmax were （5.3±1.4）,（4.2±1.2）, and （5.9±2.8） hours; t1/2 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 increased pro- portionally with the dose, the PK properties of ranolazine were linear after administration of single oral doses of 500 to 1500 mg. These dosa- ges were generally well tolerated by all the sub- jects.