Accumulation of nitidine chloride in rat heart and the underlying mechanism
(2.Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China 310058)
【Abstract】Nitidine chloride (NC) is a compound with prominent antitumor activity. To determine the potential cardiotoxicity of NC, this study was designed to investigate the distribution of NC in rat heart and the underlying mechanisms. The animal studies were approved by Institutional Animal Care and Use Committee of Zhejiang University Medical Center (2015-380-01) and were complied with the standards of animal welfare in China. At the 0.25th, 0.5th, and 2nd hour after a single intravenous injection (iv) of 5 mg·kg−1 NC, the concentration of NC in rat heart was 47.7 μg·g−1, 71.1 μg·g−1, and 63.2 μg·g−1, respectively, which was 576-fold, 1 352-fold, and 1 212-fold of that in the plasma. Our study also revealed that the NC concentration in heart was 458.5 μg·g−1 (7 336-fold of that in plasma) 2 h after the last dose in rats, after daily iv of NC at 5 mg·kg−1·d−1 for 20 successive days. Further studies showed that the accumulation of NC in MDCK-hOCT1 and MDCK-hOCT3 cells was 16.1-fold and 4.99-fold of that of the mock cells, respectively. There was no significant difference between the accumulation of NC in MDCK cells transfected with hOCTN1, hOCTN2, or hPMAT and the mock cells. Additionally, quinidine, L-tetrahydropal‐matine (L-THP) and Decynium 22, the inhibitors of OCTs, significantly decreased the accumulation of NC in primary myocardial cells and cardiac fibroblasts from neonatal rats. The results of MTT assay showed that the LC50 of NC on myocardial cells and cardiac fibroblasts was 10.9 and 10.4 μmol·L−1, respectively. Moreover, treatment of the primary myocardial cells and cardiac fibroblasts with NC (1–15 μmol·L−1) for 48 h resulted in significantly increased leakage of LDH in these cells. The results above indicated that NC could be highly accumulated in the heart, and that the accumulation was mediated by OCT1 and OCT3, but not by OCTN1, OCTN2, or PMAT. The accumulated NC had potential cytotoxicity to the primary myocardial cells and cardiac fibroblasts.
【Keywords】 nitidine chloride; cardiac accumulation; organic cation transporter 1 and 3 (OCT1, OCT3) ; cardiotoxicity;
(Translated by XING Y)
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