健康志愿者中阿德福韦酯的单、多剂量药动学研究

目的：评估健康志愿者单次、多次口服阿德福韦酯片剂(ADV)的药动学。方法：共27名健康志愿者入选本研究,其中12名受试者采用交叉、随机、开放和拉丁方设计的方法,分别单次给予ADV 5,10,30 mg,进行单剂量药动学研究。另15名受试者(其中3名服用安慰剂)采用随机、双盲、安慰剂对照设计方法,口服ADV 10 mg,qd×6 d,研究多剂量药动学。结果：口服ADV 5,10,30 mg,t_(max)的中位数为1．00,0．65,0．88 h；t_(1/2)为(10±5),(9．2±2．8),(8．4±1．4)h；c_(max)为(11±4),(25±8),(76±23)μg·L~(-1)；AUC_(0～t)为(143±52),(235±82),(715±268)μg·h·L~(-1)。单次和多次口服ADV 10 mg达稳态后,t_(max)的中位数为1．00,0．88 h；t_(1/2)为(8．1±2．0),(9．7±2．8)h；c_(max)为(22±5),(27±7)μg·L~(-1)；AUC_(0～t)为(206±53),(289±91)μg·h·L~(-1)。结论：ADV吸收迅速,c_(max)和AUC_(0～t)的增加与剂量呈正相关,连续给药未见蓄积,血药浓度d 4达稳态,主要经肾脏排泄。

Study on pharmacokinetics of single and multi-dose of oral adefovir dipivoxil tablets in healthy volunteers

AIM:To investigate the pharmacokinetics of adefovir dipivoxil (ADV) with a single and multiple-dose oral administration in Chinese healthy volunteers.METHODS:All together 27 healthy volunteers were enrolled.A randomized,cross-over study was performed in 12 volunteers with three phases separated by a washout period of 1 wk.The drug concentrations of plasma sample from them after taking ADV tablets 5,10, 30 nag were determined and the pharmacokinetic parameters were calculated.On the other hand,another 15 se- lected healthy volunteers were administrated ADV 10 nag or placebo (the ratio of ADV and placebo was 4:1) once a day for 6 d.The plasma concentrations after d 1 and d 7 and urine concentrations in 48 h after d 1 of ADV were determined by LC/MS/MS and the pharmacokinetic parameters were calculated by WinNonLin.RE- SULTS:The main pharmacokinetic parameters of ADV after oral 5,10,30 mg showed as follow,median of t_(max) were 1.00,0.65 and 0.88 h;t_(1/2) were (10±5),(9.2±2.8) and (8.5±1.4) h;c_(max) were (11±4), (25±8) and (76±23)μg·L~(-1);AUC_(0-1),were (143±52),(235±82) and (715±268)μg·h·L~(-1).The main pharmacokinetic parameters of ADV after a single oral dose (10 mg) and multiple-dose were as follow, median of t_(max) were 1.00 and 0.88h;t_(1/2) were (8.1±2.0 ) and (9.7±2.8) h;c_(max) were (22±5) and (27±7)μg·L~(-1);AUC_(0-1) were (206±53) and (289±91)μg·h·L~(-1).CONCLUSION:ADV can be absorbed rapidly and the increase of c and A UC_(0-1) are directly in positive correlation with that of ADV doses;without accumulation in plasma after multiple-dose of administration,reaching stabilization at d 4,and excreting main- ly through kidney.