摘要
本研究建立了恒河猴全血中IMM-H007及其主要活性代谢产物M1及MP的HPLC-MS/MS定量测定方法,并成功应用于恒河猴全血药代动力学研究。液相色谱分离采用Capcell PAK ADME柱(2.1 mm×100 mm,3μm,Shiseido,Japan),流动相为甲醇/水(含0.1%甲酸),梯度洗脱;质谱检测采用电喷雾(ESI)离子源,正离子模式,选择离子检测(SRM)方式测定。经方法学考证,IMM-H007及其代谢产物在恒河猴全血中线性关系良好,批内和批间精密度与准确度偏差均小于15%,回收率高且无基质效应,在样品处理、储存和分析过程中均稳定,说明该测定方法准确、可靠,可满足恒河猴全血动力学研究需要。恒河猴单次口服不同剂量IMM-H007(70、210、630 mg·kg^(-1))后,原形药IMM-H007在体内血药浓度较低,主要以活性代谢产物M1和MP的形式存在,MP的体内暴露量明显高于M1。MP在恒河猴体内动力学过程符合线性动力学特征。上述研究为新型调血脂药物IMM-H007后续临床前药理毒理和临床研究提供了可靠的参考数据。
A simple, sensitive and reliable method was developed for simultaneous quantification of IMM-H007 and its major active metabolites — M1 and MP in the blood of rhesus monkey using HPLC-MS/MS analysis. The analytes and internal standard（IS） WS070119 were separated using a Capcell PAK ADME Column（2.1 mm × 100 mm, 3 μm, Shiseido, Japan） with a gradient mobile phase of methanol/water containing 0.1% formic acid. The detection was performed in positive selected reaction monitoring（SRM） mode with electrospray ionization（ESI） source. Satisfactory linearity was obtained while the inter-and intra-assay precision and accuracy differences were no more than 15% with high recovery and good stability for the quantification, indicating the present method was specific, accurate and reliable. The method was successfully applied to the pharmacokinetic study of IMM-H007 in rhesus monkey. After single oral administration of IMM-H007（70, 210, 630 mg·kg^-1）, M1 and MP were detected in blood, while the concentration of IMM-H007 was much lower than its metabolites. The active metabolite MP with linear kinetics had a higher exposure than other analytes in vivo. The results provide an useful and reliable model for pharmacological and toxicological studies of IMM-H007 as well as its clinical application.
作者
王蕊
王宝莲
李燕
WANG Rui;WANG Bao-lian;LI Yan(Beo＇ing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China)
出处
《药学学报》
CAS
CSCD
北大核心
2018年第7期1156-1161,共6页
Acta Pharmaceutica Sinica
基金
中国医学科学院医学与健康科技创新工程经费资助项目(2017-I2M-1-010)
