西嗪伪麻缓释片人体药动学研究

 目的建立人血浆中西替利嗪和伪麻黄碱的LC-ESI-MS测定法,以研究健康志愿者口服西嗪伪麻缓释片后西替利嗪和伪麻黄碱的药动学过程。方法采用随机双交叉实验设计,12名健康志愿者分别空腹服用和进食后服用西嗪伪麻缓释片1片(每片含盐酸西替利嗪5mg、盐酸伪麻黄碱120mg);连续口服西嗪伪麻缓释片7d,每日2片,采用LC-ESI-MS测定西替利嗪和伪麻黄碱的血药浓度,估算药动学参数。结果空腹服用和进食后服用西嗪伪麻缓释片1片后西替利嗪的t_1/2为(7.6±1.0)和(7.4±0.7)h,t_max为(0.9±0.5)和(2.6±1.2)h,ρ_max为(196.3±30.1)和(154.4±28.2)μg·L^-1,AUC_0-36为(1.51±0.25)和(1.52±0.28)mg·h·L^-1;连续口服西嗪伪麻缓释片后西替利嗪的t_1/2为(7.5±0.8)h,t_max为(1.0±0.6)h,ρ_ss-max为(246.1±38.2)μg·L^-1,ρ_ss-min为(81.3±26.1)μg·L^-1,ρ_ss-av为(126.0±24.0)μg·L^-1,DF为(1.34±0.31),R为(1.39±0.18),AUC_ss为(1.51±0.29)mg·h·L^-1。空腹服用和进食后服用西嗪伪麻缓释片1片后伪麻黄碱的t_1/2为(5.2±0.4)和(5.3±0.4)h,t_max为(4.4±0.9)和(4.6±0.9)h,ρ_max为(330.2±68.3)和(341.8±61.6)μg·L^-1,AUC_0-36为(3.60±0.89)和(3.61±0.98)mg·h·L^-1;连续口服西嗪伪麻缓释片后伪麻黄碱的t_1/2为(5.3±0.6)h,t_max为(4.3±0.4)h,ρ_ss-max为(456.2±142.6)μg·L^-1,ρ_ss-min为(207.8±99.4)μg·L^-1,ρ_ss-av为(341.1±118.9)μg·L^-1,DF为(0.76±0.17),R为(1.60±0.40),AUC_ss为(4.09±1.42)mg·h·L^-1。结论所建立的人血浆中西替利嗪和伪麻黄碱的LC-ESI-MS测定方法灵敏、准确、简便。和空腹服药相比较,饮食影响西嗪伪麻缓释片中的西替利嗪的达峰浓度和达峰时间,对伪麻黄碱的药动学基本无影响。西替利嗪和伪麻黄碱在健康受试者体内不存在蓄积现象。伪麻黄碱具有缓释特征。

Study on Pharmacokinetics of Extended-release Pseudoephedrine/Cetirizine Combination Tablet in Chinese Volunteers

OBJECTIVE To develop LC-ESI-MS methods for determination of cetirizine and pseudoephedrine in human plasma and to investigate the pharmacokinetics of cetirizine and pseudoephedrine in healthy volunteers. METHODS According to a randomized two-crossover design,12 volunteers received a single oral dose of extended-release pseudoephedrine/cetirizine combination tablet (containing 5 mg cetirizine hydrochlorite and 120 mg pseudoephedrine hydrochlorite) while fasting and immediately after the consumption of a meal respectively. After the single dose design,the volunteers participated in the multiple dose design in which each volunteer received two tablets per day for seven consecutive days. The concentrations of cetirizine and pseudoephedrine in human plasma were determined by LC-ESI-MS methods. RESULTS The main pharmacokinetic parameters of cetirizine in single dose while fasting and fed state were as follows:t_1/2 were (7.6±1.0) and (7.4±0.7) h,t_max were (0.9±0.5) and (2.6±1.2) h,ρ_max were (196.3±30.1) and (154.4±28.2) μg·L^-1,AUC_0-36 were (1.51±0.25) and (1.52±0.28) mg·h·L^-1. The main pharmacokinetic parameters of cetirizine in multiple doses were as follows:t_1/2 was (7.5±0.8) h,t_max was (1.0±0.6) h,ρ_ss-max was (246.1±38.2) μg·L^-1,ρ_ss-min was (81.3±26.1) μg·L^-1,ρ_ss-av was (126.0±24.0)μg·L^-1,DF was (1.34±0.31),R was (1.39±0.18),AUC_ss was (1.51±0.29) mg·h·L^-1. The main pharmacokinetic parameters of pseudoephedrine in single dose while fasting and fed state were as follows:t_1/2 were (5.2±0.4) and (5.3±0.4) h,t_max were (4.4±0.9) and (4.6±0.9) h,ρ_max were (330.2±68.3) and (341.8±61.6) μg·L^-1,AUC_0-36 were (3.60±0.89) and (3.61±0.98) mg·h·L^-1;The main pharmacokinetic parameters of pseudoephedrine in multiple doses were as follows:t_1/2 was (5.3±0.6) h,t_max was (4.3±0.4) h,ρ_ss-max was (456.2±142.6) μg·L^-1,ρ_ss-min was (207.8±99.4) μg·L^-1,ρ_ss-av was (341.1±118.9) μg·L^-1,DF was (0.76±0.17),R was (1.61±0.40),AUC_ss was (4.09±1.42) mg·h·L^-1. CONCLUSION The methods were proved to be sensitive,accurate and convenient. As compared with the fasted condition,ρ_max of cetirizine was decreased and t_max of cetirizine was delayed under the fed state. The fatty and high protein diet had no influences on the main pharmacokinetic parameters of pseudoephedrine. There were no accumulations of cetirizine and pseudoephedrine in vivo after multiple oral doses of test tablets for 7 d. Cetirizine was immediately released and pseudoephdrine had the extended-release character from the test tablets.