抗辐射药物E0703和代谢物E0703-酮在猕猴体内的药代动力学

摘要

OBJECTIVE To develop a high performance liquid chromatography-mass spectrometry ( HPLC-MS/MS) method for simultaneous determination of E0703 and its metabolite E0703-tone and investigate pharmacokinetics of E0703 and E0703-tone in rhesus monkeys. METHODS After rhesus monkeys were po given E0703 10 mg·kg-1, blood samples were collected at different time points and pretreated by protein precipitation with acetonitrile. The super-natant diluted with deionized water was separated by HPLC on Capcell Pak C18 MG column. The mass spectrometer was operated in the positive ESI mode and detected by multiple reaction monitoring (MRM), E0703 and it's metabolite E0703-tone were determined by HPLC-MS/MS. Pharmacokinetic parameters of E0703 and E0703-tone were calculated. RESULTS The linear range of E0703 and E0703-tone was both 0.625 -500μg·L-1. The intra- and inter-day precision was <7%. The intra-and inter-day accuracy was both within ±10%. Peak concentration ( cmax) of E0703 and E0703-tone was 14. 7 and 96. 9μg·L-1, respectively. Area under concentrations (AUC) of E0703 and E0703-tone was 173.0 and 1339.7 h·μg22·L-1, and t1/2 was 6. 6 and 11. 8 h, respectively. CONCLUSION A sensitive and precise HPLC-MS/MS method is developed and validated. E0703 is metabolized to ketone metabolites (E0703-tone) in rhesus monkey. The pharmacokinetic behavior of E0703 is similar to that of E0703-tone according to concentration-time profiles. However, cmax and AUC of E0703-tone are much higher than those of E0703.%目的 建立高效液相-质谱联用( HPLC-MS/MS)测定猕猴血浆中E0703和代谢物E0703-酮的方法,并探讨E0703和代谢物E0703-酮在猕猴体内的药代动力学.方法 猕猴单次po给予E0703 10 mg·kg-1后,于不同时间点采集血浆样品.血浆样品用乙腈沉淀蛋白,经HPLC分离,质谱采用ESI离子源正离子电离和多反应检测模式(MRM)测定E0703和E0703-酮的血药浓度,并计算相关药代动力学参数.结果 E0703和E0703-酮的检测线性范围均为0.625 ～ 500 μg·L -1,日内、日间精密度均小于7％,准确度在±10％以内.E0703和E0703-酮的峰浓度(Cmax)分别为14.7和96.9μg·L-1；曲线下面积(AUC)分别为173.0和1339.7 h·μg·L-1；消除半衰期(t1/2)分别为6.6和11.8 h.结论 该液质联用定量分析方法灵敏、快速、准确.E0703和E0703-酮的血药浓度-时间曲线相似,E0703在猕猴体内迅速转化为E0703-酮,但E0703-酮的cmax与AUC远高于E0703.