盐酸丙酰左卡尼汀片在健康人体中的药代动力学研究

摘要

目的 考察盐酸丙酰左卡尼汀片在健康志愿受试者单次和多次口服给药的药代动力学及进食对其的影响.方法 单次给药时受试者分4组(0.5、1、2g、安慰剂)平行进行,多次给药1组(1g),进食影响2组(餐前给药、餐后给药)交叉进行.采用LC-MS/MS法检测丙酰左卡尼汀、乙酰左卡尼汀、左卡尼汀的浓度,采用DAS2.1.1药代动力学程序估算丙酰左卡尼汀、乙酰左卡尼汀、左卡尼汀药代动力学参数.结果 单次给药3个剂量组(0.5、1、2 g)的主要药动学参数为:丙酰左卡尼汀Cmax:(428.84±165.49)、(489.67±231.73)、(2 202.99±1 373.44)μg·L-1;AUC(0-t):(6 208.91±2 138.44)、(7 248.55±2 557.87)、(14266.30±7386.05)μg·L-1·h-1.空腹和进食后单次给药后丙酰左卡尼汀的Cmax分别为(904.23±868.38)μg·L-1和(326.95±130.97)μg·L-1;AUC(0-t)分别为(8 678.42±2 864.59)μg·L-1·h-1和(4 009.97±1736.10)μg·L-1·h-1.多次给药后丙酰左卡尼汀的 MRT为(15.03±1.28)h;Cmaxss为(778.78±342.05)μg·L-1;Cminss为(245.75±164.40)μg·L-1;AUC(0-t)及AUCbc分别为(7664.89±1 555.36)μg·L-1·h-1和(4 343.95±2 388.05)μg·L-1·h-1,Css为(638.74±129.61)μg·L-1,DF为(84.57±51.25)%.结论 单次和多次口服盐酸丙酰左卡尼汀片后盐酸丙酰左卡尼汀的药代动力学过程基本相似;在0.5~2 g剂量范围内,盐酸丙酰左卡尼汀符合线性动力学特征,多次给药后盐酸丙酰左卡尼汀代谢物在体内无蓄积现象,进食对盐酸丙酰左卡尼汀的药代动力学参数有显著影响.%Objective To evaluate the pharmacokinetics characteristics in healthy Chinese after single and multiple oral dose of propionyl levocarnitine hydrochloride by healthy volunteers on an empty stomach and after eating. Methods Four groups for the single dose( 0. 5, 1,2 g and placebo )were enrolled to do the parallel comparison; 1 group for multiple dose( 1 g )and 2 groups for eating effect( an empty stomach and after eating )to do cross comparison. LC-MS/MS was applied for detection of the concentration of propionyl levocarnitine ( PLC ),acetyl-l-carnitine( ALC )and levocarnitine( LC ). Pharmacokinetic software DAS 2. 1. 1 was used to calculate the pharmacokinetic parameters of PLC,ALC and LC. Results The pharmacokinetic parameters of single dose( 0. 5,1 and 2 g )were:PLC Cmax :( 428. 84 ± 165.49 ),( 489.67 ±231. 73),(2 202.99 ±1 373.44)μg· L-1; AUC(0_t):( 6 208.91 ±2 138. 44),(7 248.55 ±2 557.87), ( 14 266. 30 ±7 386. 05 )μg· L-1· h-1. The parameters of before and after eating for single PLC were Cmax( 904. 23 ± 868. 38 )μg· L-1 and( 326.95 ±130.97 )μg· L-1 ,AUC(0_t)( 8 678. 42 ±2 864. 59 )μg· L-1· h-1 W( 4 009. 97 ± 1 736. 10 )μg· L-1· h-1,iespectively. The parameters of multiple dose of PLC were MRT( 15. 03 ± 1. 28 )h, Cmaxss( 78. 78 ± 342. 05 )μg· L-1 , Cminss( 245. 75 ± 164.40)μg· L-1,A[/C(0_t)and A[/Cbc(7 664.89±l 555.36)μg· L-1· h-1 ,( 4 343. 95 ±2 388. 05 )μg· L-1· h-1,riespectively. Conclusion The pharmcokinetics of single and multiple dose of PLC are similar. In the dose range of 0. 5 ~ 2 g,the pk of PLC is con-sitent with the linear dynamics characteristics. After the intake of multiple dose of PLC, there is no accumulation phenomena in human body,and eating has significant influence on PLC.