LC-MS/MS测定抗肿瘤活性物质咖啡酸-3,4-二羟基苯乙酯及其在人肝微粒体中的药物代谢特点研究

摘要

To study the pharmacokinetic characteristic of antitumorcaffeic acid-3,4-dihydroxybenzylethyl (-3,4-dihydroxyphenethyl) ester (CADPE) in human liver microsomes.Human liver microsomes were incubated in vitrowith CADPE for different times.LC-MS method was applied to determine the concentrations of CADPE and its metabolites of hydroxytyrosol and caffeic acid at the designed time points.AnLC-MS analytic method was established and validated to determine the concentrations of CADPE and its metabolites hydroxytyrosol and caffeic acid inhuman liver microsomes.CADPE metabolism showed single compartment model and it's half-life (T1/2) was 0.72 ± 0.09 h.The time to peak (Tmax) and the half-life(T1/2) for hydroxytyrosol was 1.3 ± 0.3 h,3.97 ± 0.58 h,respectively.Hydroxytyrosol metabolism showed single compartment characteristic.The relationship of caffeic acid concentration and time was logarithmic.The concentration of caffeic acid gradually increased and finally reached steady state with the gradual metabolism of CADPE.This study clarified the pharmacokinetic characteristics of CADPE and its metabolites hydroxytyrosol and caffeic acid in human liver microsomes.The data obtained also provided scientific basis for the further investigation of the pharmacokinetic characteristics of CADPE in animals and human.%本实验研究抗肿瘤活性物质咖啡酸-3,4-二羟基苯乙酯(CADPE)在体外肝微粒体中的代谢特点.通过CADPE在体外人肝微粒体培养不同时间后,用液质联用测定CADPE及其代谢产物咖啡酸和羟基酪醇在各时间点的药物浓度,描绘各物质的药-时曲线,确定CADPE的代谢特点.CADPE在肝微粒体中的代谢呈单室模型,半衰期(T1/2)为0.72 ±0.09 h.CADPE代谢产物羟基酪醇的达峰时间(Tmax)为1.30 ±0.30 h,半衰期(T1/2)为3.97±0.58 h,咖啡酸浓度与时间的关系成对数关系.明确了CADPE及其代谢产物羟基酪醇和咖啡酸在体外人肝微粒体中的药代动力学特征,为进一步深入研究CADPE在动物及人体内的药代动力学特征提供了科学依据.