国产盐酸地尔硫缓释胶囊的药代动力学的研究

Study on Pharmacokinetics of Domstic Diltiazem Hydrochloride Sustaind-Release Capsule in Chinese Healthy Volunteers

目的：评价地尔硫Zhuo缓释胶囊在中国人体内的药代动力学特性。方法：对12名健康志愿者进行了国产盐酸地尔硫Zhuo缓释胶囊单剂量和多剂量的体内药代动力学的研究。地尔硫Zhuo及代谢产物N-去甲基地尔硫Zhuo(Ma)和去乙酰基地尔硫Zhuo(M1)的血药浓度采用高效液相色谱法测定。结果：国产盐酸地尔硫Zhuo缓释胶囊在中国人体内的血药浓度曲线无论是单剂量还是多剂量均呈一级释放一级吸收的单室模型。主要动力学参数；单剂量试验。消除速率常数ke为0.094±0.027^-1;tmax为5.80±1.14h;Cmax为42.90±17.91μg·L^-1,AUC0-∞54.20±246.41μg·h·L^-1。多剂量试验；消除速率常数ke为0.080±0.028h^-1;tmax为4.58±1.14h;Cmax为151.6±71.27μg·h·L^-1;AUC0-τ分别为1271.1±574.1μg·h·L^-1。Css'min为98.68±42.88μg·L^-1;DF为37.80%±20.34%。结论：比较单剂量用药和多剂量用药的药代动力学参数，提示地尔硫Zhuo多剂量用药可能在体内出现明显的蓄积，临床用药时应注意药物不良反应的监护。

OBJECTIVE:To evaluate the pharmacokinetical characteristic ofdomesticdiltiazem sustained-release capsule.METHODS:To study pharmacokinetics on asingle and multiple oral dose of domestic diltiazem sustained-release capsule in l2health volunteers in vivo, and to determined plasma concentration-time curves ofmetabolites (deacetyldiltiazem and N-demethyldiltiazem) of diltiazem. Theconcentrations of parent and metabolites of diltiazem in plasma were determined byHPLC. RESULTS:The results showed that the plasma concentration-time curves ofsingle and multiple dose of domestic diltiazem sustained-release capsules werefitted to a one-compartment open model with first order release and first orderabsorption. The primary pharmacokinetics parameters: single oral dose group:kewas 0.094±0.027 h-1,tmax was5.80±l.l4h, Cmax was 42.90±l7.9lμg.h.L-1, andAUC0-∞was654.20±246.41μg.h.L-1. Multiple oral dose group:ke was 0.080±0.028h-1,tmax was4.58±l.l4h.Cmax was l5l.6±7l.27μg.L-1,AUC0-r, was 127l.1±574.lμg.h.L-l, Css'min was 98.68±42.88μg.h.L-1, and DFwas 37.80 %± l 20.34 %. CONCLUSION:To compare the pharmacokinetics parameters of single dose with ones of multipledose, it was indicated that diltiazem in body was accumulated obviously in multipledose,we should pay attention to ADR care in clinical treatment.