Effects of Total Phenolic Acid and Total Alkaloid of Ligusticum chuanxiong Hort. on Pharmacokinetics of Temozolomide in Blood, Brain and Tumor of C6 Glioma Rats and Its Mechanism
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
Abstract：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 AUC0→∞ in blood of C6 glioma rats when compared with TMZ group, but tmax, Cmax and CL/F changed to different degrees. TA and TPA in Ligusticum chuanxiong Hort significantly increased the AUC0→∞ 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.
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. 川芎总酚酸和总生物碱对替莫唑胺在C6胶质瘤大鼠血液和脑及瘤内药动学的影响及机制研究[J]. 中国药学杂志, 2022, 57(13): 1089-1098.
SHUAI Shu-yuan, LIU Shan-shan, ZHENG Qin, YANG Ming, YUE Peng-fei, HU Peng-yi, ZHANG Guo-song, LIU Xiao-jin, ZUMULAITI·Wubuli. Effects of Total Phenolic Acid and Total Alkaloid of Ligusticum chuanxiong Hort. on Pharmacokinetics of Temozolomide in Blood, Brain and Tumor of C6 Glioma Rats and Its Mechanism. Chinese Pharmaceutical Journal, 2022, 57(13): 1089-1098.
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2022, Vol. 57 
