阿德福韦酯在大鼠体内的药代动力学和组织分布特性研究

Study on pharmacokinetics and tissue distribution of adefovir dipivoxil in rats

目的研究阿德福韦酯在大鼠的体内过程特性及绝对生物利用度,为临床合理用药提供依据。方法大鼠随机分组,分别一次性灌胃给药阿德福韦酯3.0,1.0,0.3 mg·Kg^(-1),静脉注射0.54 mg·Kg^(-1),采用高效液相色谱法检测阿德福韦在生物样品中的含量,并计算药代动力学参数。大鼠口服阿德福韦酯后于0.7,3,6h测定各组织的药物浓度。口服阿德福韦酯1.0mg·Kg^(-1),24h内收集胆汁,测定药物胆汁排出率。用平衡透析法测定药物的人血清蛋白结合率。结果该药药代动力学过程符合无滞后时间的二室模型,高、中、低三个剂量的AUC_(0-∞)分别为10.7±1.19,3.91±0.315,1.54±0.074μg·mL^(-1)·h;t_(max)在0.62~0.76 h之间,C_(max)与给药剂量成正比,分别为2.26±0.299,0.758±0.0529,0.388±0.0269μg·mL^(-1);t_(1/2)为5.0~7.3 h;绝对生物利用度为分别为(53±5.2)%,(51±8.1)%,(42±6.0)%。静脉注射给药阿德福韦后t_(1/2)(k_e)为7.5±0.16h,AUC_(0-∞)为6.35±1.58μg·mL^(-1)·h。母体药物阿德福韦在组织中分布情况为肾>肝>胃,其他组织中的浓度均远低于血浆中浓度。胆汁累积排泄率低于2%,在0.10~4.0μg·mL^(-1)的浓度范围内,人血清蛋白结合率为<5%。结论阿德福韦酯在动物体内迅速吸收,消除半衰期较长,胆汁不是该药的主要排泄途径,血液及主要脏器无药物蓄积。阿德福韦是生物样品中检测到的唯一代谢产物。

OBJECTIVE The pharmacokinetic properties of adefovir dipivoxil were studied in rats.METHODS Upon oral administration of adefovir dipivoxil at 0.3,1.0,3.0 mg Kg^(-1),plasma samples were obtained at intervals during the 24 h postdosing and were analyzed for adefovir concentrations by HPLC.Then the pharmacokinetic parameters were caculated.Adefovir levels in rat tissuses at different time intervals(0.7,3,6h) were determined after oral administration at 1.0 mg Kg^(-1).The bilitary accumulative excretion was determined after oral dose of 1.0 mg Kg^(-1).The rat of serum protein binding in human was determined by equilibrium dialysis method.RESULTS The pharmacokinetic process of rats fitted to two compartments model.At 0.3,1.0,3.0 mg Kg^(-1) doses,C_(max)were 0.388±0.0269,0.758±0.0529,and 2.26±0.299 g mL^(-1) and occurred between 0.62 and 0.73 h;t_(1/2)β were between 5.0and 7.3 h;AUC_((0~∞)) were 1.54,3.91,10.7(μg · mL^(-1)) · h and the bioavailabilities of adefovir were 42%,51%,and 53%respectively.The bilitary accumulation excretion in rats was less than 2%within 24 h after oral administration.In vitro binding of adefovir to human serum proteins is < 5%over the adefovir concentration range of 0.10 to 4.0 μg.mL^(-1).In main tissues,the adefovir concentration was followed as in order C_(kideny)> C_(liver)> C_(stomach).CONCLUSIONS Adefovir dipivoxil was rapidly absorbed in rats with a longer t_(1/2)β.There was no accumulation in blood and main tissues of adefovir.Adefovir was the only metabolite formed of adefovir dipivoxil,which could be detected in plasma,tissue and bilitary samples.