Pan Jie, Lu Yuan, Zhang Shuai, Li Yueting, Sun Jia, Liu Hua Chunhua, Gong Zipeng, Huang Jing, Cao Chuang, Wang Yonglin, Li Yongjun, Liu Ting
State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, School of Pharmacy, Guizhou Medical University, Guiyang, China.
Key Laboratory of Pharmaceutics of Guizhou Provincial, School of Pharmacy, Guizhou Medical University, Guiyang, China.
Xenobiotica. 2020 Oct;50(10):1251-1257. doi: 10.1080/00498254.2020.1765049. Epub 2020 May 13.
Hepatocellular carcinoma (HCC) is a malignancy of liver cells. Recent studies have shown that HCC patients often have changes in the activities of transporters and metabolic enzymes, which can considerably affect drug pharmacokinetics and lead to drug toxicity. Doxorubicin (DOX) has been frequently administered in chemotherapy for HCC, but to our knowledge, the effects of HCC on the pharmacokinetics of DOX are unknown.In the present study, following intravenous administration of DOX in diethylnitrosamine-induced HCC rats, the plasma concentration was determined by a UPLC/MS/MS method. The expression of metabolic enzyme and transporters (p-gp, cbr1 and slc22a16) was analyzed by qRT-PCR and western blot.The results showed that the pharmacokinetic parameters AUC, , and of DOX were markedly increased, the and CL were significantly decreased in HCC rats. The expression of cbr1 and slc22a16 was markedly decreased, while p-gp was significantly upregulated in HCC rats.These findings suggest that HCC could significantly alter the pharmacokinetic profile of DOX, which may be associated with the decreased expression of cbr1 and slc22a16 rather than the upregulation of p-gp expression.
肝细胞癌（HCC）是一种肝细胞恶性肿瘤。最近的研究表明，HCC患者的转运蛋白和代谢酶活性常常发生变化，这会显著影响药物的药代动力学并导致药物毒性。阿霉素（DOX）常用于HCC的化疗，但据我们所知，HCC对DOX药代动力学的影响尚不清楚。在本研究中，给二乙基亚硝胺诱导的HCC大鼠静脉注射DOX后，采用超高效液相色谱/串联质谱法测定血浆浓度。通过qRT-PCR和蛋白质印迹法分析代谢酶和转运蛋白（p-gp、cbr1和slc22a16）的表达。结果显示，HCC大鼠中DOX的药代动力学参数AUC、 、 和 显著增加， 和CL显著降低。HCC大鼠中cbr1和slc22a16的表达显著降低，而p-gp显著上调。这些发现表明，HCC可显著改变DOX的药代动力学特征，这可能与cbr1和slc22a16表达降低而非p-gp表达上调有关。
