Determination of zofenopril and its active metabolite zofenoprilat by a new derivative LC-MS method and their pharmacokinetics in healthy Chinese volunteers / 中国药科大学学报

ABSTRACT

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 zofenopri-lat 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 parameters of both the parent drug and the active metabolite were simultaneously determined by derivative LC-MS method using p-bromophenacyl bromide (p-BPB) as the derivative reagent. Results: After the single oral administrations of 15, 30, and 60 mg of zofeno-pril calcium, there was no significant difference in the t_(1/2) of both zofenopril and zofenoprilat among the three do-ses. The values of AUC_(0-24h) and c_(max) for both zofenopril and zofenoprilat showed the good linearities to the dosage over the dose range from 15 mg to 60 mg. There were no significant differences in AUC_(0-24h) and c_(max) for both com-pounds between female and male volunteers. After multiple oral administration( 30 mg once daily for 6 days ), the average steady state plasma concentration( c_(av)) for zofenopril was (5. 07 ±1. 06) ng/mL with the degree of fluctu-ation (DF) of 14. 26 ± 2. 94. The c_(av) for zofenoprilat was (6. 28 ± 1. 87) ng/mL with the DF of 11. 61 ±4. 68. The accumulation index values for zofenopril and zofenoprilat were 0. 94 ± 0. 31 and 0. 83±0. 13, respec-tively. Conclusion: Both zofenopril and zofenoprilat were demonstrated of linear kinetics after single administra-tion and showed no accumulation after multiple administration of the test zofenopril calcium tablets. There was significant difference in the pharmacokinetic characteristics for zofenopril calcium between healthy Chinese and European volunteers.