Ji Yun, Zhan Ying, Jiang Cuihua, Jiang Xiao, Gao Meng, Liu Wei, Li Yue, Wang Junhu, Wang Qingqing, Cona Marlein Miranda, Yao Nan, Wang Xiaoning, Fang Zhijun, Yin Zhiqi, Zhang Jian, Sun Ziping, Ni Yicheng
Department of Natural Medicinal Chemistry, China Pharmaceutical University , Nanjing, Jiangsu Province , P.R. China .
J Drug Target. 2014 May;22(4):304-12. doi: 10.3109/1061186X.2013.867962. Epub 2013 Dec 13.
Hypericin (Hyp) is newly recognized as a necrosis avid agent, but its poor solubility imposes a great hindrance in clinical application. The aim of this paper was to explore sodium cholate (NaCh) as a potential solvent for Hyp and assess the targetability of (131)I-Hyp in rat necrosis models. Hyp solubility in NaCh solutions was evaluated by equilibrium solubility measurement. Biodistribution of (131)I-Hyp in NaCh solutions and mixed organic solvents was investigated in rat models of liver and muscle necrosis examined with MRI and SPECT/CT in vivo. In addition, pharmacokinetics of (131)I-Hyp in NaCh solutions was studied in healthy rats. Results showed NaCh could improve Hyp solubility and (131)I-Hyp incubated in NaCh solutions/rat plasma was stable up to 120 h. On SPECT/CT images at 24 h post injection, liver infarction location appeared as hot spots. Liver necrosis-to-liver ratios were 12.2, 10.0, 9.6 and 8.2 in 60, 15, 2 mmol/L of NaCh solutions and organic solvents, and muscle necrosis-to-liver ratios were 11.1, 10.1, 7.7 and 7.4, respectively. Pharmacokinetics study revealed t(1/2)z (11.93, 8.96 h, p > 0.05) and AUC (0-∞) (421.21, 553.34 MBq/L h, p < 0.05) of (131)I-Hyp in 2, 60 mmol/L of NaCh solutions, respectively. In conclusion, NaCh was an effective cosolvent, and the necrosis avidity of NaCh-dissolved (131)I-Hyp/Hyp was demonstrated.
金丝桃素（Hyp）最近被认为是一种对坏死组织具有亲和力的药物，但其溶解度低给临床应用带来了很大障碍。本文旨在探索胆酸钠（NaCh）作为Hyp的潜在溶剂，并评估131I - Hyp在大鼠坏死模型中的靶向性。通过平衡溶解度测量评估Hyp在NaCh溶液中的溶解度。在大鼠肝脏和肌肉坏死模型中，利用MRI和SPECT/CT在体内研究了131I - Hyp在NaCh溶液和混合有机溶剂中的生物分布。此外，还在健康大鼠中研究了131I - Hyp在NaCh溶液中的药代动力学。结果表明，NaCh可提高Hyp的溶解度，且在NaCh溶液/大鼠血浆中孵育的131I - Hyp在120小时内保持稳定。注射后24小时的SPECT/CT图像上，肝脏梗死部位显示为热点。在60、15、2 mmol/L的NaCh溶液和有机溶剂中，肝脏坏死与肝脏的比值分别为12.2、10.0、9.6和8.2，肌肉坏死与肝脏的比值分别为11.1、10.1、7.7和7.4。药代动力学研究显示，在2、60 mmol/L的NaCh溶液中，131I - Hyp的t(1/2)z分别为11.93、8.96小时（p > 0.05），AUC(0 - ∞)分别为421.21、553.34 MBq/L·h（p < 0.05）。总之，NaCh是一种有效的助溶剂，证明了NaCh溶解的131I - Hyp/Hyp对坏死组织具有亲和力。
