地尔硫活性代谢产物的药动学

目的　研究地尔硫主要活性代谢产物体内的药动学 ,评价代谢产物在地尔硫临床治疗中的作用。方法　以 8名健康志愿者为对象 ,采用了单剂量 ( 90mg)和多剂量 ( 90mg ,bid)的给药方案 ,于给药后不同时间取血 ,血中地尔硫、去乙酰基地尔硫 (M1)和N 去甲基地尔硫 (Ma)的浓度采用高效液相法测定。结果　药 时曲线显示地尔硫经代谢 ,很快转化为去乙酰基地尔硫和N 去甲基地尔硫 ,多剂量显示明显的累积效应。药动学参数显示了地尔硫、去乙酰基地尔硫和去甲基地尔硫消除速率依次下降。地尔硫的曲线下面积 ,多剂量是单剂量的 2倍 ,但两个代谢产物的仅为 0 .79和 0 .5 8倍 ;代谢产物与地尔硫的曲线下面积比值的变化 ,M 1从单剂量的 1.3降为多剂量的 0 .72 ,Ma从单剂量的 1.0 4降为多剂量的0 .32 ,表明多剂量时Ma的量明显减少。结论　以上结果提示多剂量时存在着代谢酶的抑制作用 ,尤其是对地尔硫的代谢成Ma的途径的抑制作用较M1更明显 ,可能也是引起地尔硫的蓄积效应的原因之一。建议当临床长期使用地尔硫时 ,应适当地监测血药浓度。

Study on pharmacokinetics of active metabolites of diltiazem in healthy volunteers

OBJECTIVE To study the pharmacokinetics of the main active metabolites of diltiazem(DTZ).To evaluate the role of the metabolites of diltiazem,deacetyldiltiazem (M1) and N monodesmethyldiltiazem (Ma) in clinical treatment.METHODS Eight healthy volunteers were given diltiazem 90 mg by single and multiple oral dose and the blood samples were collected at different time after administration.The plasma concentrations of M1 and Ma were determined by HPLC.RESULTS Diltiazem was quickly metabolized into its metabolites,M1 and Ma.The levels of M1 were higher than that of Ma.The multiple dose administration showed significant accumulation effect.The pharmacokinetic parameters showed that the elimination rates of DTZ,M1 and Ma declined successively.The ratios of the areas under curve of DTZ ,M1 and Ma after multiple dose compared with that after single dose were 2,0.79 and 0.58 respectively.AUC M1 /AUC DTZ dropped from 1.3 of single dose to 0.72 of multiple dose.AUC Ma /AUC DTZ dropped from 1.04 of single dose to 0.32 of multiple dose.The data showed that the amount of Ma decreased evidently.CONCLUSION It indicated that the inhibition of metabolic enzyme,especially,the inhibitory effect on DTZ changed into Ma was more significant than that on DTZ changed into M1,which may cause accumulation effect after multiple dose.The plasma concentrations of diltiazem are suggested to be monitored when diltiazem is dosed for a long term.