左乙拉西坦片健康人体药动学

Pharmacokinetics of levetiracetam in healthy volunteers

目的:建立检测人血清中左乙拉西坦浓度的高效液相色谱(HPLC)法,并研究健康受试者单剂量及多剂量口服左乙拉西坦片后的药动学特征。方法:32名健康志愿者按体质量指数随机分组,每组8人,男女各半,分别单次口服左乙拉西坦片250,500,750mg和多次口服左乙拉西坦片bid,每次250mg,连续6d,用HPLC法测定血清中药物的浓度,并计算药动学参数。结果:经DAS2.0软件拟合计算,单次给药低、中、高剂量组主要药动学参数tmax、Cmax、AUC0-36、t1/2分别为(1.4±1.2),(1.2±1.2)和(1.8±1.1)h,(7.2±1.7),(14.6±3.2)和(20.2±4.9)mg.L-1,(61±11),(138±28),(202±35)mg.L-1.h,(5.5±0.8),(6.1±0.8),(6.0±1.6)h,多次给药组的tmax、Cmax、Cmin、t1/2、Vd、CL、AUCss、Cav分别是(0.9±0.5)h,(21.3±1.8)mg.L-1,(7.5±1.7)mg.L-1,(5.8±0.9)h,(0.38±0.04)L.Kg-1、(0.0460±0.0005)L.h-1.Kg-1,(138±9)mg.L-1.h,(11.5±0.8)mg.L-1。结论:左乙拉西坦片口服给药符合一级药动学房室模型,服用剂量和AUC0-36间有良好的线性关系;多次给药与相同剂量单次给药后的药动学参数差异无显著性,左乙拉西坦片多次给药无明显蓄积。

OBJECTIVE To establish a HPLC method for determination of serum concentration of levetiracetam and to study the pharmacokinetics of the drug in healthy volunteers after single dose and multiple dose administration. METHODS Thirty-two volunteers were divided into four groups randomly, each group included four men and four women. In the single dose design, the volunteers of three groups received either a single dose of 250, 500,750 mg levetiracetam. The volunteers of another group received 250 mg levetiracetam twice daily for 6 days. The serum concentrations were determined by HPI.C method and the pharmacokinetic parameters of levetiracetam were calculated. RESULTS The main pharmacokinetics parameters of the drug after single oral dose of 250,500,750 mg were tmax：（1.4±1.2）,（1.2±1.2）,（1.8±1.1）h;Cmax：（7.2±1.7）,（14.6± 3.2） ,（20. 2 ± 4. 9） mg·L^-1;AUC0-36：（61 ± 11）,（138 ± 28） ,（202 ± 35） mg·L^-1 ·h;t1/2 ： （5. 5 ± 0. 8）, （6. 1 ± 0. 8） and （6.0 ± 1.6）h. After oral dosing of 250mg twice daily for 6 days, the main pharmacokinetics parameters of the drug were tmax： （0. 9 ± 0. 5）h,Cmax ： （21.3 ± 1.8） mg·L^-1, Cmin ： （7. 5 ± 1.7） mg·L^-1, t1/2 ： （5.8 ± 0. 9） h, Vd ： （0. 38 ± 0. 04） L·Kg^-1 , CL（0. 046 0 ± 0. 000 5）L·h^-1·Kg^-1,AUCss：（138±9）mg·L^-1·h,Cav：（11.5±0.8）mg·L^-1. CONCLUSION The pharmacokinetic resuhs show that levetiracetam exhibits first order kinetic characteristics. The pharmacokinetic parameters of levetiracetam do not differ remarkably after 500mg single and multiple doses and there is no accumulation in serum after oral dosing of 250 mg twice daily for 6days.