霉酚酸与代谢物的血药浓度测定及基于UGTs酶的性别相关的药动学研究  

Measurement of Mycophenolic Acid and Its Glucuronide in the Plasma and Study on Gender-related Pharmacokinetics Based on UGTs Enzymes

作　　者：吴莉莉 夏晨 李乔希 刘碧浩 张红雨[1] 王妍[1] WU Lili;XIA Chen;LI Qiaoxi;LIU Bihao;ZHANG Hongyu;WANG Yan(Department of Pharmacy,The First People's Hospital of Foshan,Foshan 528000,China;Foshan Blink Biomedical Research Co.,Ltd.,Foshan 528251,China)

机构地区：[1]佛山市第一人民医院药学部,广东佛山528000 [2]佛山市布林克生物医药研究有限公司,广东佛山528251

出　　处：《中国现代应用药学》2023年第19期2659-2664,共6页Chinese Journal of Modern Applied Pharmacy

基　　金：2022年度佛山市卫生健康局医学科研课题(20220379);广东省中医药局面上项目(20241299);广东省医院药学研究基金(2024A18)。

摘　　要：目的应用UPLC同时测定大鼠血浆中霉酚酸(mycophenolic acid,MPA)及代谢物霉酚酸葡萄糖醛酸苷(MPA-glucuronide,MPAG)的血药浓度,并对其性别相关的药动学特征进行分析研究。方法选取12只SD大鼠,雌雄各半,灌胃给予90 mg·kg^(-1)·d^(-1)霉酚酸酯,于给药后不同时间点眼眶采血,血浆样本经液液萃取处理,采用UPLC测定血浆中MPA及代谢物MPAG的药物浓度。选用Waters BEH C_(18)色谱柱,采用梯度洗脱程序,流动相为乙腈(A)-0.1%甲酸水溶液(B),流速为0.35 mL·min^(-1),检测波长为266 nm,柱温为40℃,使用DAS 2.0软件计算药动学参数。结果MPA和MPAG的血药浓度分别在0.31~160μg·mL^(-1)(R^(2)=0.9998)和0.62~320μg·mL^(-1)(R^(2)=0.9994)内线性关系良好,建立的MPA和MPAG的分析测定方法均符合方法学验证要求。雌性大鼠体内MPA和MPAG的AUC_(0-t)和C_(max)均高于雄性大鼠(P<0.05或P<0.01),染料木素[葡萄糖醛酸转移酶(UDP-glucuronosyltransferases,UGTs)底物]和MPA在雄性大鼠肝微粒体酶中的代谢速率均明显快于雌性大鼠肝微粒体酶。结论该方法灵敏、准确、专属性强,适用于MPA及代谢物MPAG的血药浓度测定,大鼠体内MPA和MPAG的药动学具有性别差异性,可能与UGTs活性的性别差异有关。OBJECTIVE To establish a UPLC detection method for simultaneous determination of mycophenolic acid(MPA)and its glucuronide(MPAG)in plasma of rats,and to investigate gender-related pharmacokinetic characteristics of mycophenolic acid.METHODS Twelve SD rats(half male and half female)were intragastrically administrated with 90 mg·kg^(−1)·d^(-1)mycophenolate acetate,and blood was collected from periorbital vein at different time points after administration.Plasma samples were extracted by liquid-liquid extraction and drug concentrations of MPA and metabolite MPAG in plasma were determined using UPLC.The method was developed using Waters BEH C_(18)column.The gradient elution was performed at a flow rate of 0.35 mL·min^(-1)with the mobile phase acetonitrile solution(A)-0.1%formic acid aqueous solution(B).The detection wavelength was at 266 nm and column oven temperature was maintained at 40℃.The pharmacokinetic parameters were calculated by using DAS 2.0 software.RESULTS The linear relationship between peak area and concentrations of MPA and MPAG were good in the ranges of 0.31-160μg·mL^(-1)(R^(2)=0.9998)and 0.62−320μg·mL^(-1)(R^(2)=0.9994),respectively.Analytical methods of MPA and MPAG all met the requirements of the methodology.Pharmacokinetic parameters AUC_(0-t)and C_(max)of MPA and MPAG in female rats were higher than that in male rats(P<0.05 or P<0.01).In addition,the metabolic rate of genistein[UDP-glucuronosyltransferases(UGT)s substrate]and MPA in male rat liver microsomes were significantly faster than that in female rat liver microsomes.CONCLUSION This developed UPLC method is sensitive,accurate and specific,which is suitable to detect the concentrations of MPA and MPAG in the plasma.The pharmacokinetics of MPA and MPAG in rats are gender different,which may be related to the sex difference of UGTs metabolic enzyme activity.

关 键 词：霉酚酸 霉酚酸葡萄糖醛酸苷 UGTS 性别差异 

分 类 号：R969.1[医药卫生—药理学]