Accumulation of nitidine chloride in rat heart and the underlying mechanism
10.16438/j.0513-4870.2019-0001
- VernacularTitle:氯化两面针碱在大鼠心脏中的积聚及其机制研究
- Author:
Cui LI
1
;
Ying-chun CHEN
2
;
Qing-quan ZENG
2
;
Shao-wei LEI
1
;
Hui ZHOU
2
;
Hui-di JIANG
2
;
Li-ping LI
2
Author Information
1. Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China; Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
2. Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Publication Type:Research Article
- Keywords:
nitidine chloride;
cardiac accumulation;
organic cation transporter 1 and 3 (OCT1, OCT3);
cardiotoxicity
- From:
Acta Pharmaceutica Sinica
2019;54(5):913-918
- CountryChina
- Language:Chinese
-
Abstract:
Nitidine chloride (NC) is a compound with prominent anti-tumor activity. To determine potential cardiotoxicity of NC, this study was designed to investigate the distribution of NC in rat heart and the underlying mechanism. The animal studies were approved by Institutional Animal Care and Use Committee of Zhejiang University Medical Center (2015-380-01) and complied with the standards of animal welfare in China. At 0.25, 0.5 and 2 h after a single intravenous injection (iv) of 5 mg·kg-1 NC, the concentrations of NC in rat heart were 47.7, 71.1 and 63.2 μg·g-1 respectively, which were 576, 1 352 and 1 212 folds of that in plasma. This study also revealed that the NC concentration in heart was 458.5 μg·g-1 (7 336 folds of that in plasma) at 2 h after the last dose in rats, after daily iv administration of NC at 5 mg·kg-1·day-1 for successive 20 days. Further studies showed that the accumulations of NC in MDCK-hOCT1 and MDCK-hOCT3 cells were 16.1 and 4.99 folds higher than that of the mock cells, respectively. There is no significant difference between the accumulations of NC in MDCK cells transfected with hOCTN1, hOCTN2 or hPMAT and the mock cells. Additionally, quinidine, L-tetrahydropalmatine and Decynium 22, the inhibitors of OCTs, clearly reduced the accumulations of NC in primary cardiomyocytes and cardiac fibroblasts from neonatal rats. MTT assay showed that the LC50 of NC on cardiomyocytes and cardiac fibroblasts were 10.9 and 10.4 μmol·L-1, respectively. Moreover, treatment of the primary cardiomyocytes and cardiac fibroblasts with NC (1～15 μmol·L-1) for 48 h resulted in significantly increased LDH enzyme leakage. These results indicated that NC can be highly accumulated in the heart, and accumulation is mediated by OCT1 and OCT3, but not by OCTN1, OCTN2 and PMAT. The accumulated NC has potential cytotoxicity as shown in the results from primary cardiomyocytes and cardiac fibroblasts.
