衍生化LC-MS法测定人体内佐芬普利及其活性代谢物以及药代动力学研究

Determination of zofenopril and its active metabolite zofenoprilat by a new derivative LC-MS method and their pharmacokinetics in healthy Chinese volunteers

目的:建立衍生化LC-MS法同时测定佐芬普利及其活性代谢物佐芬普利拉的人体血药浓度,研究健康中国受试者单次和多次口服佐芬普利钙片后,佐芬普利和佐芬普利拉的药代动力学特征。方法:10名健康受试者先分别单次口服15,30和60 mg受试制剂,然后连续6 d多次口服30 mg受试制剂,以对溴苯甲酰甲基溴为衍生化试剂,采用衍生化LC-MS法同时测定人血浆中佐芬普利及其活性代谢物佐芬普利拉的浓度,并计算二者的药代动力学参数。结果:健康受试者分别单次口服佐芬普利片后,3个剂量组的佐芬普利和佐芬普利拉的半衰期相近;在15～60 mg剂量范围内,佐芬普利和佐芬普利拉的AUC0-24 h和cmax均与剂量呈良好的线性关系,且均不存在性别差异。多剂量(每日1次,每次30 mg)连续给药6 d后,佐芬普利的平均稳态血药浓度cav为(5.07±1.06)ng/mL,血药浓度波动度DF为14.26±2.94,蓄积常数为0.94±0.31。佐芬普利拉的cav为(40.31±5.40)ng/mL,DF为11.61±4.68,蓄积常数为0.83±0.13。结论:佐芬普利及活性代谢物佐芬普利拉在中国人体内均呈线性药代动力学特征,多次给药后在体内均无蓄积;二者在中国人体内的药代动力学特征和代谢与欧洲人之间存在种族差异。

Aim:A new derivative LC-MS method was developed for the simultaneous determination of zofenopril and its active metabolite zofenoprilat to investigate the pharmacokinetic characteristics of zofenopril and zofenoprilat in healthy Chinese volunteers after single and multiple oral doses of zofenopril calcium tablets.Methods:Ten Chinese healthy volunteers were given three single oral doses of 15,30,and 60 mg,respectively,and consecutively the multiple doses of 30 mg.The concentration and pharmacokinetic paramet...