摘要
目的 研究川芎中的总生物碱(TA)、总酚酸(TPA)与替莫唑胺(TMZ)配伍前后对TMZ在C6胶质瘤大鼠血、脑、肿瘤中药动学的影响及相关作用机制。方法 将大鼠C6脑胶质瘤模型随机分为3组,分别单次灌胃给与TMZ、TMZ+TA、TMZ+TPA,于不同时间点处死大鼠取血、脑、肿瘤组织,处理后用液质连用(LC-MS/MS)测定血、脑、肿瘤组织中TMZ含量,统计分析配伍前后药动学参数的差异;另取C6胶质瘤大鼠,分别连续5 d灌胃给与TMZ、TMZ+TA、TMZ+TPA,最后一次给药后处死大鼠取含瘤全脑组织,处理后采用蛋白印迹法测定occludin、claudin-5、ZO-1和caveolin-1蛋白水平。结果 TMZ分别与TA、TPA配伍后,C6胶质瘤大鼠血中AUC _(()(0→∞))与TMZ单用组相比无显著变化,t_(max)、c_(max)、CL/F发生不同程度的改变。川芎中的TA、TPA均能显著提高TMZ脑内AUC _(()(0→∞)),显著增加脑血分布比,使得TMZ脑靶向性指数DTI_(脑)分别为1.35、1.24。TMZ与TA、TPA配伍后,C6胶质瘤大鼠肿瘤内主要药动学参数与TMZ单用组相比无显著性差异(P>0.05),TMZ肿瘤靶向性指数DTI_(瘤)分别为1.07、1.12。与空白对照组相比,川芎TA、TPA均能显著抑制紧密连接蛋白occludin、claudin-5蛋白表达,显著增加caveolin-1蛋白表达,TMZ分别与川芎中的TA、TPA配伍后,可显著增加caveolin-1蛋白表达,显著抑制occludin和claudin-5蛋白表达,但对ZO-1蛋白水平无显著性影响。结论 川芎中的TA、TPA增加TMZ入脑的机制可能与其下调C6胶质瘤大鼠脑内紧密连接蛋白occludin和claudin-5,上调caveolin-1蛋白水平有关。
OBJECTIVE To investigate the effects of total alkaloid(TA),total phenolic acid(TPA) in Ligusticum chuanxiong Hort.on the pharmacokinetics of temozolomide(TMZ) in blood,brain and tumor of C6 glioma rats and its related mechanism.METHODS The C6 glioma rats were randomly divided into 3 groups,which were given TMZ,TMZ+TA and TMZ+TPA by intragastric administration for a single time,respectively.Then the rats were sacrificed at different time to collect blood,brain and tumor.The content of TMZ in blood,brain and tumor was measured by LC-MS/MS after treatment,and the differences of pharmacokinetic parameters before and after compatibility were analyzed statistically.Then the C6 glioma rats were orally administrated of TMZ,TMZ+TA and TMZ+TPA for five consecutive days,respectively.After the last administration,the rats were sacrificed and the whole brain tissue containing the tumor was collected.After treatment,the protein levels of occludin,claudin-5,ZO-1 and caveolin-1 were determined by Western blotting.RESULTS After TMZ was combined with TA and TPA,there was no significant change in AUC_(0→∞) in blood of C6 glioma rats when compared with TMZ group,but t_(max),C_(max) and CL/F changed to different degrees.TA and TPA in Ligusticum chuanxiong Hort significantly increased the AUC_(0→∞) of TMZ in brain,significantly increased the brain-blood distribution ratio,and made the TMZ brain targeting index DTI up to 1.35 and 1.24,respectively.After TMZ was combined with TA and TPA,there was no significant difference in the main pharmacokinetic parameters in tumor of C6 glioma rats compared with TMZ group(P>0.05).The tumor targeting index DTI of TMZ was 1.07 and 1.12,respectively.Compared with control group,TA and TPA of Ligusticum chuanxiong Hort.significantly inhibited the expression of tight junction proteins occludin and claudin-5,and significantly increased the expression of caveolin-1.Combined with TA or TPA,TMZ could significantly increase the expression of caveolin-1,and significantly inhibit the expression of occludin and claudin-5,but had no significant effect on the ZO-1 protein level.CONCLUSION TA and TPA in Ligusticum chuanxiong Hort increasing the accumulation of TMZ in the brain might be related to the down-regulation of occludin and claudin-5 in the brain of C6 gioma rats,and the up-regulation of caveolin-1 protein.
作者
帅书苑
刘姗姗
郑琴
杨明
岳鹏飞
胡鹏翼
张国松
刘小金
祖木来提·伍布力
SHUAI Shu-yuan;LIU Shan-shan;ZHENG Qin;YANG Ming;YUE Peng-fei;HU Peng-yi;ZHANG Guo-song;LIU Xiao-jin;ZUMULAITI·Wubuli(Key Laboratory of Modern Preparation of Chinese Medicine,Ministry of Education,State Key Laboratory of Innovation Drug and Efficient Energy-Saving Pharmaceutical Equipment,Jiangxi University of Chinese Medicine,Nanchang 330004,China)
出处
《中国药学杂志》
CAS
CSCD
北大核心
2022年第13期1089-1098,共10页
Chinese Pharmaceutical Journal
基金
国家自然科学基金项目资助(81760714)
江西省博士后项目资助(2017KY08)
江西中医药大学博士科研启动基金项目资助(2018WBZR003)。
关键词
川芎
总酚酸
总生物碱
替莫唑胺
药动学
紧密连接
Ligusticum chuanxiong Hort.
total phenolic acid
total alkaloid
temozolomide
pharmacokinetics
tight junction
