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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。
Objective To study the pharmacokinetics of the major active metabolites of diltiazem and to evaluate the role of metabolites in the clinical treatment of diltiazem. Methods A total of eight healthy volunteers were enrolled in this study. The single-dose (90mg) and multiple-dose (90mg bid) dosing regimens were used. Blood samples were taken at different times after administration. Diltiazem, The concentrations of thiomersal (M1) and N-demethoxydim (Ma) were determined by high performance liquid chromatography. Results The time course showed that diltiazem was metabolized and rapidly converted to deacetyl diltiazem and N desmethyl diltiazem, with multiple doses showing a significant cumulative effect. The pharmacokinetic parameters showed that the elimination rates of diltiazem, desacetyl diltiazem and desmethyl dimulfide decreased in turn. The area under the curve for diltiazem was more than twice as much as the single dose, but only 0.79 and 0.58 times for both metabolites; changes in the area under the curve for metabolites to diltiazem , M 1 decreased from 1.3 for single dose to 0.72 for multiple dose, and Ma decreased from 1.0 4 for single dose to 0.32 for multiple dose, indicating a significant reduction in the amount of Ma at multiple doses. Conclusions The above results suggest that there is a metabolic enzyme inhibition effect at multiple doses. In particular, inhibition of the pathway of diltiazem metabolism to Ma is more pronounced than that of M1, which may be one of the reasons for the accumulation effect of diltiazem . It is recommended that when long-term clinical use of diltiazem, blood levels should be properly monitored.